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.

Epistaxis and other haemorrhagic events associated with the smoking cessation medicine varenicline: a case series from two national pharmacovigilance centres.

PURPOSE: To present a case series of haemorrhagic events associated with varenicline identified from the New Zealand (NZ) and Netherlands national pharmacovigilance centres and propose a possible mechanism for these adverse events. METHODS: Reports of epistaxis and other haemorrhagic events (in all system organ classes excluding gynaecological) associated with varenicline were identified and assessed in both the NZ Intensive Medicines Monitoring Programme (IMMP) and the Netherlands Pharmacovigilance Centre Lareb (Lareb). Additional reports were identified from the World Health Organisation Uppsala Monitoring Centre (WHO-UMC) datasets, and these also underwent causality assessment. RESULTS: A total of 30 reports of haemorrhagic events were identified by the NZ IMMP (16 reports) and Lareb (14 reports). Six cases of epistaxis were identified, and four patients had a positive dechallenge on withdrawal of varenicline, suggesting a causal association. Another five reports of gingival bleeding were identified, with three patients having a positive dechallenge. Another patient who experienced haemoptysis while taking varenicline had a positive dechallenge and a positive rechallenge. In the WHO datasets, a further 49 reports of epistaxis, 39 reports of haemoptysis and 21 reports of thrombocytopenia were identified. A plausible mechanism for haemorrhagic events associated with varenicline may be a result of interaction with the serotonin (5-HT) receptor system and transporter. CONCLUSIONS: This is the first specific investigation of haemorrhagic events associated with varenicline. The results of our assessment of reports identified by two national pharmacovigilance centres suggest that there may be causal relationship between varenicline and these adverse events.

[Current concepts in tobacco cessation and prevention]. / A dohányzás megelozése és a leszokás támogatásának lehetoségei.

In the recent years, for oral care in general, both improving oral hygiene and tobacco use cessation have been identified as necessary measures to gain and maintain long-term periodontal health. This growing evidence has given the dental team a whole new task to tackle when achieving and maintaining oral health with their patients. In order to support dental patients to quit tobacco use, it is helpful for the clinician to have a clear understanding of the genesis of 'tobacco use disease' in general. At present, the evidence-based method for tobacco use cessation consists of professional counselling on behavioural change using the so called "5A Method" (Ask, Advise, Assess, Assist and Arrange") in combination with pharmacotherapy. A suitable model for behavioural support in tobacco use cessation would help patients to move from one stage to the next. People who want to quit the smoking habit do not always participate in carefully controlled nicotine withdrawal programs, e.g. in linear fashion and from start to finish. Nevertheless, simple instructions - like those offered in the "Assist" (to help) and "Arrange" (to organize follow-up visits) - can be valuable tools for dental professionals supporting their patients to quit smoking. On the basis of significant evidence on the recovery of the oral mucosa and the periodontal tissue following tobacco use cessation, a new task has been emerged in dentistry: the role of oral health professionals providing counselling for patients who ought to quit tobacco use.

Effect of platelet-rich plasma on a rabbit model of nicotine-compromised bone healing.

PURPOSE: This study aimed to evaluate the effects of platelet-rich plasma (PRP) on nicotine-compromised bone healing. MATERIALS AND METHODS: Fifteen adult New Zealand white rabbits were implanted with 1.5-g time-release nicotine pellets. Bilateral mandibular distraction osteogenesis was then performed. Autologous PRP was injected into 1 side of the distraction regenerate, whereas physiologic saline solution was injected into the contralateral side as a control. Five rabbits were killed on day 5 of active distraction, on day 11 of active distraction, and in week 2 of consolidation, respectively. RESULTS: In the PRP the platelet enrichment was 14.63 ± 3.081-fold of that in whole blood. Plain radiography and micro-computed tomography assessment showed no significant difference between the PRP injection and control sides. Histologic examination showed more disorganized distraction tissue on the PRP injection side. CONCLUSIONS: PRP injection at an early stage of active distraction does not significantly enhance bone healing in the nicotine-compromised rabbit model of mandibular lengthening.

Effect of nicotine exposure on the rate of orthodontic tooth movement: A meta-analysis based on animal studies.

BACKGROUND: Nicotine exposure has been reported to modify bone cell function and the osseous metabolism with potential effects on the rate of orthodontic tooth movement. OBJECTIVES: To systematically investigate and quantitively synthesize the most recent available evidence from animal studies regarding the effect of nicotine exposure on the rate of orthodontic tooth movement. SEARCH METHODS: Unrestricted searches in 7 databases and hand searching were performed until July 2020 (PubMed, Central, Cochrane Database of Systematic Reviews, SCOPUS, Web of Science, Arab World Research Source, ProQuest Dissertations and Theses Global). SELECTION CRITERIA: We searched for controlled studies on healthy animals investigating the effect of nicotine on the rate of orthodontic tooth movement. DATA COLLECTION AND ANALYSIS: Following study retrieval and selection, relevant data was extracted and the risk of bias was assessed using the SYRCLE's Risk of Bias Tool. Exploratory synthesis and meta-regression were carried out using the random effects model. RESULTS: From the initially identified records, 5 articles meeting the inclusion criteria were selected and no specific concerns regarding bias were identified. Quantitative data synthesis showed that the rate of orthodontic tooth movement in the nicotine exposed rats was higher than in the control group animals (2 weeks of force application; 0.317 mm more movement in nicotine exposed rats; 95% Confidence Interval: 0.179-0.454; p = 0.000). No effect of the concentration or the duration force application was demonstrated following exploratory meta-regression. CONCLUSION: Rats administered with nicotine showed accelerated rates of orthodontic tooth movement. Although, information from animal studies cannot be fully translated to human clinical scenarios, safe practice would suggest that the orthodontist should be able to identify patients exposed to nicotine and consider the possible implications for everyday clinical practice.

A Time-to-Event Model Relating Integrated Craving to Risk of Smoking Relapse Across Different Nicotine Replacement Therapy Formulations.

Smoking increases the risk of cancer and other diseases, causing an estimated 7 million deaths per year. Nicotine replacement therapy (NRT) reduces craving for smoking, therefore, increasing an individual's probability to remain abstinent. In this work, we for the first time quantitatively described the relationship between craving and smoking abstinence, using retrospectively collected data from 19 studies, including 3 NRT formulations (inhaler, mouth spray, and patch) and a combination of inhaler and patch. Smokers motivated to quit were included in the NRT or placebo arms. Integrated craving (i.e., craving over a period of time) was assessed with 4-category, 5-category, or 100-mm visual analogue scale. The bounded integer model was used to assess latent craving from all scales. A time-to-event model linked predicted integrated craving to the hazard of smoking relapse. Available data included 9,323 adult subjects, observed for 3 weeks up to 2 years. At the study end, 9% (11% for NRT and 5% for placebo), on average, remained abstinent according to the protocol definition. A Gompertz-Makeham hazard best described the data, with a hazard of smoking relapse decreasing over time. Latent integrated craving was positively related to the hazard of smoking relapse, through a sigmoidal maximum effect function. For the same craving, being on NRT was found to reduce the hazard of relapse by an additional 30% compared with placebo. This work confirmed that low craving is associated with a high probability of remaining smoking abstinent and that NRT, in addition to reducing craving, increases the probability of remaining smoking abstinent.

Behavioral effects of nicotine withdrawal differ by genetic strain in male and female adolescent rats.

INTRODUCTION: Gender and ethnicity are powerful predictors of initiation and maintenance of cigarette smoking in adults but less is known about their role in smoking in adolescents. Consistent with human studies, rat models also reveal sex and strain differences in response to nicotine administration. METHODS: This research examined nicotine withdrawal behaviors in 96 adolescent, male and female, Sprague Dawley (SD) and Long Evans (LE) rats. Rats received seven days continuous subcutaneous infusion of saline or 3.16 mg/kg nicotine via Alzet osmotic minipumps. Behavioral observations were made before, during, and after saline or nicotine administration. Occurrences of six specific behaviors were quantified: abnormal posture or movement, abnormal grooming, whole-body shakes, ptosis, empty-mouth chewing/teeth chattering, and diarrhea. RESULTS: SD male and female rats that received nicotine displayed significantly more withdrawal behaviors 1 and 2 days after cessation of nicotine administration compared with rats that had received saline. LE male rats that received nicotine displayed significantly more withdrawal behaviors 1 day but not 2 days after cessation of nicotine administration compared with males that received saline. LE females showed no significant withdrawal behaviors after cessation of nicotine administration. CONCLUSION: Results indicate that nicotine withdrawal in adolescent rats depends on sex and strain.

Effect of nicotine on gene expression of angiogenic and osteogenic factors in a rabbit model of bone regeneration.

PURPOSE: This study aims to evaluate the influence of nicotine on the gene expression of osteogenic and angiogenic factors in bone regeneration by use of a nicotine-compromised rabbit model of mandibular lengthening. MATERIALS AND METHODS: Thirty adult New Zealand white rabbits were randomly assigned to the nicotine group or the control group. The total nicotine or placebo exposure time for all animals was 7 weeks. Unilateral mandibular distraction osteogenesis was performed. Five animals in each group were sacrificed at day 5, day 11, and day 18, respectively, after commencement of active distraction. The distraction regenerate samples were harvested, and the messenger ribonucleic acid expression of bone transforming growth factor beta(1), platelet-derived growth factor A, and basic fibroblast growth factor was assayed by real-time polymerase chain reaction analysis. RESULTS: The messenger ribonucleic acid expression of transforming growth factor beta(1), platelet-derived growth factor A, and basic fibroblast growth factor was significantly inhibited by nicotine exposure at a variety of time points. CONCLUSIONS: The presence of nicotine inhibited the gene expression of angiogenic and osteogenic factors resulting in compromised bone regeneration.

Oral ulceration due to chronic use of Nicorette gum: case report.

Oral ulceration is a common presentation in a dental clinic. These ulcers may be acute or chronic, based on the duration of symptoms. The etiology of oral ulceration can range from trauma to squamous cell carcinoma. It is the responsibility of the dentist to differentiate the various etiologies of oral ulceration for proper management. This case report is presented to remind dentists that the long-term use of Nicorette gum should be considered in the differential diagnosis of chronic oral ulcers.

[The influence of tobacco-smoke components on alpha-ketopropionic acid in the pulp of front and rear teeth of chronic smokers].

The composition of cigarette-smoke is relatively well known in spite of its tremendous complexity. But the analysis of cigarette smoke toxicological influence on biochemical components of tooth enamel, dentine and pulpe is not completely study. The present study was designed to characterize the pulpe biochemical component (alpha-ketopropionic acide) by acute serous pulpit. The total number of 140 patients, age 35-40 (Tobacco-smokers 80, non-smokers - 60) have been investigated. The results suggested, that tobacco-smokers chisel tooth and molars contains less alpha-ketopropionic acide than non-smokers individuals. These studies support the hypothesis of cigarette smoke important role in the tooth support mechanisms. The biochemical activity and function of tooth proteins and amino acids composition must by compared to concentration of tobacco-smoke components.

Behavioral effects of nicotine withdrawal in adult male and female rats.

Nicotine withdrawal may differ between men and women but clinical reports are inconsistent. Two experiments were conducted to examine behavioral effects of nicotine withdrawal in male and female adult rats in dimly-lit and brightly-lit environments. Ninety-six Sprague-Dawley male and female rats received 7 days continuous subcutaneous infusion via ALZET osmotic minipumps filled with saline or 3.16 mg/kg/day nicotine hydrogen tartrate expressed as base. Behavioral observations were made before, during, and after drug administration. During observations, occurrences of empty-mouth-chewing, whole-body-shakes, abnormal grooming, abnormal posture/movement, diarrhea, ptosis, eyeblinks, and any other abnormal behaviors were counted. Cessation of nicotine administration upon pump removal caused a significant increase in withdrawal behaviors in males and females in both environments. In the dimly-lit environment, females showed more withdrawal behavior than males; there was no sex difference in the brightly-lit environment. Males that had received nicotine displayed more withdrawal behavior in the brightly-lit environment than in the dimly-lit environment, while females that had received nicotine displayed similar amounts of withdrawal behavior in both environments. Behavioral symptoms of withdrawal may be more affected by the environment in male rats than in female rats. These experiments are the first to compare nicotine withdrawal in adult male and female rats.

Nicotine impairs distraction osteogenesis in the rat mandible.

Distraction osteogenesis (DO) has gained clinical acceptance as a surgical technique for treatment of congenital craniomaxillofacial deficiencies requiring skeletal expansion. The use of this technique elsewhere requires more information on overcoming difficult clinical settings, for which new animal models will be needed. The aim of this study was to develop and validate a model of impaired DO of the rat mandible with nicotine. Twenty rats underwent a right vertical mandibular body osteotomy, after which distraction began with custom-made percutaneous devices and a 3-day latency period, 6-day distraction (0.25 mm twice daily) and 30 days of neutral fixation. Rats received either nicotine or placebo slow-release pellets. Specimens were analysed after removal of the devices for quantitative radiographic bone fill, amount of bone advancement and histological features. The mean radiographic bone-fill score with nicotine treatment was 75% of that with placebo (P=0.0036). The nicotine-treated rats had less (49%) elongation than the placebo-treated controls (P=0.0008). Histological analysis demonstrated less bone, vascularity and cellular activity in nicotine-treated rats. This study shows that nicotine reproducibly inhibits osteogenesis, vascularity and bone lengthening in mandibular DO.

Tobacco smoking and surgical healing of oral tissues: a review.

It is believed that the crew of Columbus had introduced tobacco from the 'American India' to the rest of the world, and tobacco was attributed as a medicinal plant. It was often used to avert hunger during long hours of work. But in reality, tobacco causes various ill effects including pre-malignant lesions and cancers. This article aims at reviewing the literature pertaining to the effect of tobacco smoking upon the outcome of various surgical procedures performed in the oral cavity. Tobacco affects postoperative wound healing following surgical and nonsurgical tooth extractions, routine maxillofacial surgeries, implants, and periodontal therapies. In an experimental study, bone regeneration after distraction osteogenesis was found to be negatively affected by smoking. Thus, tobacco, a peripheral vasoconstrictor, along with its products like nicotine increases platelet adhesiveness, raises the risk of microvascular occlusion, and causes tissue ischemia. Smoking tobacco is also associated with catecholamines release resulting in vasoconstriction and decreased tissue perfusion. Smoking is believed to suppress the innate and host immune responses, affecting the function of neutrophils--the prime line of defense against infection. Thus, the association between smoking and delayed healing of oral tissues following surgeries is evident. Dental surgeons should stress on the ill effects of tobacco upon the routine postoperative healing to smoker patients and should aid them to become tobacco-free.

'Real-world' compensatory behaviour with low nicotine concentration e-liquid: subjective effects and nicotine, acrolein and formaldehyde exposure.

AIMS: To compare the effects of (i) high versus low nicotine concentration e-liquid, (ii) fixed versus adjustable power and (iii) the interaction between the two on: (a) vaping behaviour, (b) subjective effects, (c) nicotine intake and (d) exposure to acrolein and formaldehyde in e-cigarette users vaping in their everyday setting. DESIGN: Counterbalanced, repeated measures with four conditions: (i) low nicotine (6 mg/ml)/fixed power; (ii) low nicotine/adjustable power; (iii) high nicotine (18 mg/ml)/fixed power; and (iv) high nicotine/adjustable power. SETTING: London and the South East, England. PARTICIPANTS: Twenty experienced e-cigarette users (recruited between September 2016 and February 2017) vaped ad libitum using an eVic Supreme™ with a 'Nautilus Aspire' tank over 4 weeks (1 week per condition). MEASUREMENTS: Puffing patterns [daily puff number (PN), puff duration (PD), interpuff interval (IPI)], ml of e-liquid consumed, changes to power (where permitted) and subjective effects (urge to vape, nicotine withdrawal symptoms) were measured in each condition. Nicotine intake was measured via salivary cotinine. 3-Hydroxypropylmercapturic acid (3-HPMA), a metabolite of the toxicant acrolein, and formate, a metabolite of the carcinogen formaldehyde, were measured in urine. FINDINGS: There was a significant nicotine concentration × power interaction for PD (P < 0.01). PD was longer with low nicotine/fixed power compared with (i) high nicotine/fixed power (P < 0.001) and (ii) low nicotine/adjustable power (P < 0.01). PN and liquid consumed were higher in the low versus high nicotine condition (main effect of nicotine, P < 0.05). Urge to vape and withdrawal symptoms were lower, and nicotine intake was higher, in the high nicotine condition (main effects of nicotine: P < 0.01). While acrolein levels did not differ, there was a significant nicotine × power interaction for formaldehyde (P < 0.05). CONCLUSIONS: Use of a lower nicotine concentration e-liquid may be associated with compensatory behaviour (e.g. higher number and duration of puffs) and increases in negative affect, urge to vape and formaldehyde exposure.

[Impact of tobacco use on the periodontium--an update (I)--Part 1: Epidemiologic und pathogenetic aspects of tobacco-related periodontal diseases]. / Einfluss des Tabakkonsums auf das Parodont--ein Update (I). Teil 1: Epidemiologische und pathogenetische Aspekte tabakbedingter Schädigungen am Parodont.

This literature review represents the second in a series of articles from the Swiss task force "Smoking--Intervention in the private dental office" on the topic "tobacco use and dental medicine". In this article, the epidemiological background as well as some pathogenetic processes are described and discussed critically for tobacco-related periodontal diseases. Earlier publications confirmed tobacco consumption as a risk factor for periodontal diseases. Over the last few years, oral health research has significantly contributed to the understanding of the mechanisms leading to the deterioration of the hard and soft tissues supporting the teeth. With the recording of the number of cigarettes smoked per day and the amount of years tobacco was used, a dose response relationship was established. Various, potentially significant pathogenic effects of tobacco-related substances may exist on the periodontal tissues, the immune response system or the composition of the oral flora. Moreover, there is reference that tobacco consumption may change the genetically determined susceptibility for periodontal diseases.

The role of the dental team in preventing and diagnosing cancer: 4. Risk factor reduction: tobacco cessation.

UNLABELLED: Tobacco use contributes to many oral and general health disorders.While cigarette smoking is the most hazardous and prevalent form of tobacco use in the industrialized countries, consideration also needs to be given to non-cigarette use such as bidi smoking in India, reverse smoking by several rural populations and use of snuff and chewing tobacco. CLINICAL RELEVANCE: Health professionals should encourage and aid cessation of tobacco use as a part of prevention of oral and other cancers.

Nicotine withdrawal in adolescent and adult rats.

Previous research with animal models has demonstrated that adolescent rats display heightened sensitivity to the reinforcing and stimulant effects of nicotine relative to adult rats. Little work has focused on the response of adolescent rats to measures of nicotine withdrawal. To test the hypothesis that adolescent rats may be differentially sensitive to withdrawal relative to their adult counterparts, the present study was designed to compare precipitated withdrawal in adolescent and adult rats following chronic nicotine administration. Adult and adolescent rats were prepared with subcutaneous osmotic minipumps that delivered either saline or nicotine (9 mg/kg per day, salt; N =12 per group). All rats were challenged with the nicotinic receptor antagonist mecamylamine (1.5 mg/kg) on day 7 of chronic nicotine treatment. Twenty minutes after the injection, overt somatic signs of withdrawal (i.e., eye blinks, writhes, body shakes, teeth chatter, gasps, and ptosis) were recorded for 10 min. Adult rats were observed on postnatal day 73-77, and adolescent rats were tested on postnatal day 36-40. The results revealed a robust increase in mecamylamine-induced withdrawal signs in adult rats receiving chronic nicotine relative to adult rats receiving saline. In contrast, mecamylamine did not precipitate withdrawal signs in adolescent rats receiving chronic nicotine. These results indicate that there is decreased sensitivity to the somatic aspects of nicotine withdrawal in adolescent rats that may maximize the reinforcing effects of nicotine during adolescence by minimizing the aversive effects of abstinence.

The long-term effect of nicotine on the oral mucosa.

AIMS: Although nicotine replacement therapy (NRT) has been used to aid smoking cessation for the last 20 years, little information exists on the effect of nicotine products on the oral mucosa, particularly with regard to the direct effect at the site of application. This study aimed to assess the oral safety of a new sublingual tablet containing 2 mg nicotine with regard to lesions at the site of application. DESIGN: Prospective follow-up to 12 months of smokers using the 2-mg sublingual tablet over a period of 3-6 months. SETTING: A smoking cessation programme. PARTICIPANTS: Thirty smokers. MEASUREMENTS: Oral mucosa was inspected and photographed at each visit. At 6 months, subjects were asked for consent to take a biopsy from the site of application. FINDINGS: Spontaneous smoking cessation outcome at 12 months was 27% allowing for lapses. At baseline 21 mucosal lesions were diagnosed in 15 subjects. After 6 months eight lesions were observed in six subjects. The predominant diagnosis at all visits was melanin pigmentation. Eight subjects had lesions in the floor of the mouth during the 6-month medication period, all of which appeared in the first 1-6 weeks of treatment. By the 6-month visit all such lesions had resolved. The local symptoms were all mild and tolerable. CONCLUSION: The sublingual tablet appears to be a safe form of administration of nicotine with mild and transient effects on the floor of the mouth.

A randomized, double-blind, placebo-controlled clinical evaluation of a nicotine sublingual tablet in smoking cessation.

AIMS: Evaluation of the clinical efficacy and safety of a nicotine 2-mg sublingual tablet in smoking cessation. DESIGN: A randomized, double-blind, placebo-controlled study of smokers using the 2-mg tablet for 3-6 months with follow-up to 12 months. Dosing was established according to baseline nicotine dependence, scored on the Fagerström Tolerance Questionnaire (FTQ): FTQ > or = 7, two tablets/hour (maximum 40/day); FTQ < 7, one tablet/hour (maximum 20/day). SETTING: Smoking cessation programme in a department of oral and maxillofacial surgery. PARTICIPANTS: A total of 247 adult smokers, smoking > or = 10 cigarettes/day for > or = 3 years, of whom 123 received active and 124 placebo treatment. The study was powered to detect difference at 6 months. MEASUREMENTS: Efficacy and safety were evaluated at 6 weeks and 3, 6 and 12 months. Self-reported abstinence was verified by exhaled CO < 10 p.p.m. FINDINGS: Success rates for complete abstinence (no slips after 2 weeks) for active vs. placebo were 50% vs. 29% at 6 weeks, 42% vs. 23% at 3 months, 33% vs. 18% at 6 months and 23% vs. 15% at 12 months (p < 0.001, 0.001, 0.005 and p = 0.14), respectively. Craving during the first 8 days was significantly reduced among highly dependent smokers on active treatment compared to placebo. Baseline mucosal lesions among abstinent subjects were reduced during the treatment period and at the non-treatment follow-up. Adverse events were mild and tolerable, the most common being irritation and soreness in the mouth and throat. CONCLUSION: The nicotine sublingual tablet increased the smoking cessation rate compared to placebo, reduced craving in highly dependent smokers and was well tolerated.