Child-resistant and tamper-resistant packaging: A systematic review to inform tobacco packaging regulation.

OBJECTIVE: We aimed to investigate the effects of special packaging (child-resistant, adult-friendly) and tamper-resistant packaging on health and behavioral outcomes in order to identify research gaps and implications for packaging standards for tobacco products. METHODS: We searched seven databases for keywords related to special and tamper-resistant packaging, consulted experts, and reviewed citations of potentially relevant studies. 733 unique papers were identified. Two coders independently screened each title and abstract for eligibility. They then reviewed the full text of the remaining papers for a second round of eligibility screening. Included studies investigated a causal relationship between type of packaging or packaging regulation and behavioral or health outcomes and had a study population composed of consumers. Studies were excluded on the basis of publication type, if they were not peer-reviewed, and if they had low external validity. Two reviewers independently coded each paper for study and methodological characteristics and limitations. Discrepancies were discussed and resolved. RESULTS: The review included eight studies: four assessing people's ability to access the contents of different packaging types and four evaluating the impact of packaging requirements on health-related outcomes. Child-resistant packaging was generally more difficult to open than non-child-resistant packaging. Child-resistant packaging requirements have been associated with reductions in child mortality. CONCLUSIONS: Child-resistant packaging holds the expectation to reduce tobacco product poisonings among children under six.

Research Priorities, Measures, and Recommendations for Assessment of Tobacco Use in Clinical Cancer Research.

There is strong evidence that cigarette smoking causes adverse outcomes in people with cancer. However, more research is needed regarding those effects and the effects of alternative tobacco products and of secondhand smoke, the effects of cessation (before diagnosis, during treatment, or during survivorship), the biologic mechanisms, and optimal strategies for tobacco dependence treatment in oncology. Fundamentally, tobacco is an important source of variation in clinical treatment trials. Nevertheless, tobacco use assessment has not been uniform in clinical trials. Progress has been impeded by a lack of consensus regarding tobacco use assessment suitable for cancer patients. The NCI-AACR Cancer Patient Tobacco Use Assessment Task Force identified priority research areas and developed recommendations for assessment items and timing of assessment in cancer research. A cognitive interview study was conducted with 30 cancer patients at the NIH Clinical Center to evaluate and improve the measurement items. The resulting Cancer Patient Tobacco Use Questionnaire (C-TUQ) includes "Core" items for minimal assessment of tobacco use at initial and follow-up time points, and an "Extension" set. Domains include the following: cigarette and other tobacco use status, intensity, and past use; use relative to cancer diagnosis and treatment; cessation approaches and history; and secondhand smoke exposure. The Task Force recommends that assessment occur at study entry and, at a minimum, at the end of protocol therapy in clinical trials. Broad adoption of the recommended measures and timing protocol, and pursuit of the recommended research priorities, will help us to achieve a clearer understanding of the significance of tobacco use and cessation for cancer patients.

E-cigarettes and cancer patients.

The increasing popularity and availability of electronic cigarettes (i.e., e-cigarettes) in many countries have promoted debate among health professionals as to what to recommend to their patients who might be struggling to stop smoking or asking about e-cigarettes. In the absence of evidence-based guidelines for using e-cigarettes for smoking cessation, some health professionals have urged caution about recommending them due to the limited evidence of their safety and efficacy, while others have argued that e-cigarettes are obviously a better alternative to continued cigarette smoking and should be encouraged. The leadership of the International Association for the Study of Lung Cancer asked the Tobacco Control and Smoking Cessation Committee to formulate a statement on the use of e-cigarettes by cancer patients to help guide clinical practice. Below is this statement, which we will update periodically as new evidence becomes available.

Medicaid coverage and utilization of covered tobacco-cessation treatments: the Arkansas experience.

BACKGROUND: Although most Medicaid programs have some coverage for tobacco-cessation treatments, little is known about how well the covered treatments are utilized among Medicaid enrollees. PURPOSE: To examine the impact of Arkansas Medicaid coverage of tobacco-cessation treatment on utilization of FDA-approved tobacco-cessation pharmacotherapies and counseling services by Medicaid enrollees. METHODS: This study used Arkansas Medicaid administrative claims data from October 1, 2003, to June 30, 2008. Trend changes in the following monthly measures were examined: (1) total number of pharmacy claims for each covered pharmacotherapy; (2) total number of medical claims for counseling services; and (3) total number of unique enrollees who received each type of covered tobacco-cessation treatment. Average unit of defined daily dose and days with treatment stratified by tobacco-cessation products within 180 days after the first tobacco-cessation treatment were examined for intensity of treatment. Data collection was finished in 2009 and analysis was completed in 2011. RESULTS: By June 30, 2008, a total of 12,673 enrollees received some tobacco-cessation treatments, and 77% of them received pharmacotherapies only. Implementation of the coverage expansion generated an initial increase in utilization of tobacco-cessation medications but quickly declined after 3 months. Utilization increased again when varenicline was added, but also decreased sharply after 6 months. Patterns of monthly claims for counseling services appeared to be inconsistent with the policy change. CONCLUSIONS: Medicaid coverage alone may have limited sustained effect on increasing utilization of the covered tobacco-cessation treatments among Medicaid enrollees.

Epidemiology of lung cancer: smoking, secondhand smoke, and genetics.

The link between smoking and development of lung cancer has been demonstrated, not only for smokers but also for those exposed to secondhand smoke. Despite the obvious carcinogenic effects of tobacco smoking, not all smokers develop lung cancer, and conversely some nonsmokers can develop lung cancer in the absence of other environmental risk factors. A multitude of genetic factors are beginning to be explored that interact with environmental exposure to alter the risk of developing this deadly disease. By more fully appreciating the complex interrelationship between genetics and other risks the development of lung cancer can be more completely understood.

Risk of second primary cancer among esophageal cancer patients: a pooled analysis of 13 cancer registries.

BACKGROUND: The objective of this study is to assess the risk of second primary cancers following a first primary esophageal cancer as well as the risk of esophageal cancer as a second primary, following first primary cancers of other sites. METHODS: The present investigation is a multicenter study of 13 population-based cancer registries in Europe, Australia, Canada, and Singapore. To assess excess occurrence of second cancers after esophageal cancers, we calculated standardized incidence ratios (SIR) by dividing the observed numbers of second cancers by the expected number of cancers calculated from the accumulated person-years and the age-, sex-, calendar period-, and registry-specific first primary cancer incidence rates. RESULTS: During the study period, 959 cases of second primary cancers occurred after an initial esophageal cancer, resulting in a SIR of 1.15 (95% confidence interval, 1.08-1.22). Second primary stomach cancers were associated with first primary esophageal adenocarcinomas (SIR, 2.13; 95% confidence interval, 1.26-3.37) and second primary cancers of the oral cavity and pharynx (6.68; 5.33-8.26), stomach (1.53; 1.14-2.01), larynx (3.24; 1.88-5.18), lung (1.55; 1.28-1.87), kidney (1.88; 1.18-2.85), and thyroid (2.92; 1.18-6.02) were associated with first primary squamous cell carcinomas of the esophagus. An excess of esophageal cancer as a second primary were observed following first primary cancers of the aerodigestive tract, female breast, cervix, testis, bladder, Hodgkin's lymphoma, and non-Hodgkin lymphoma. CONCLUSION: We observed associations of esophageal cancer with second primary head and neck cancers and lung cancer regardless of years of follow-up, which may suggest that common risk factors play a role in multiple tumor development.

Cytisine for smoking cessation: a research agenda.

Cytisine has a molecular structure somewhat similar to that of nicotine and varenicline. The concept for the new smoking cessation drug varenicline was based partly on cytisine. Like varenicline, cytisine is a partial agonist of nicotinic acetylcholine receptors, with high affinity for alpha4beta2 receptors. Cytisine has been used since the 1960s as a smoking cessation drug in Eastern and Central Europe, but has remained largely unnoticed elsewhere. Three placebo-controlled trials, conducted in East and West Germany in the 1960s and 1970s, suggest that cytisine, even with minimal behavioural support, may be effective in aiding smoking cessation. Cytisine tablets are very inexpensive to produce and could be a more affordable treatment than nicotine replacement, bupropion and varenicline. There is however a dearth of scientific research on the properties of cytisine, including safety, abuse liability and efficacy. This paper seeks to identify research priorities for molecular, animal and clinical studies. In particular, new studies are necessary to define the nicotinic receptor interaction profile of cytisine, to establish its pharmacokinetics and pharmacodynamics in humans, to determine whether animals self-administer cytisine, and to ascertain whether cytisine is safe and effective as a smoking cessation drug. Potentially, this research effort, contributing to wider use of an inexpensive drug, could save many lives.

Safety profile of a nicotine lozenge compared with that of nicotine gum in adult smokers with underlying medical conditions: a 12-week, randomized, open-label study.

BACKGROUND: Nicotine polacrilex lozenges deliver 25% to 27% more nicotine compared with equivalent doses of nicotine polacrilex gum. The increased nicotine exposure from the lozenge has raised questions about the relative safety of the lozenge and gum. OBJECTIVE: The objective of this study was to compare the safety profiles of the 4-mg nicotine lozenge and 4-mg nicotine gum in smokers with selected label-restricted diseases. METHODS: This was a multicenter, randomized, open-label study in adult smokers with heart disease, hypertension not controlled by medication, and/or diabetes mellitus. Patients were randomized in a 1:1 ratio to receive the 4-mg nicotine lozenge or 4-mg nicotine gum. Safety assessments were made at baseline and at 2, 4, 6, and 12 weeks after the start of product use. RESULTS: Nine hundred one patients were randomized to treatment, 447 who received the lozenge and 454 who received the gum (safety population). The majority were women (52.7%). Patients' mean age was 53.9 years, their mean weight was 193.9 pounds, and they smoked a mean of 25.2 cigarettes per day at baseline. Five hundred fifty-three patients, 264 taking the lozenge and 289 taking the gum, used the study product for > or =4 days per week during the first 2 weeks (evaluable population). The nicotine lozenge and nicotine gum were equally well tolerated, despite increased nicotine exposure from the lozenge. The incidence of adverse events in the 2 groups was similar during the first 2 weeks of product use (evaluation population: 55.3% lozenge, 54.7% gum), as well as during the entire study (safety population: 63.8% and 58.6%, respectively). Stratification of patients by sex, age, extent of concurrent smoking, extent of product use, and severity of adverse events revealed no clinically significant differences between the lozenge and gum. The most common adverse events were nausea (17.2% and 16.1%; 95% CI, -3.7 to 6.0), hiccups (10.7% and 6.6%; 95% CI, 0.5 to 7.8), and headache (8.7% and 9.9%; 95% Cl, -5.0 to 2.6). Serious adverse events were reported in 11 and 13 patients in the respective groups. Fewer than 6% of patients in either group were considered by the investigator to have a worsening of their overall disease condition during the study. The majority of patients (>60%) experienced no change in their disease status from baseline. CONCLUSION: The 4-mg nicotine lozenge and 4-mg nicotine gum had comparable safety profiles in these patients with label-restricted medical conditions.

Nicotine patch and lozenge are effective for women.

It has been hypothesized that women may be less likely to obtain therapeutic benefit from nicotine replacement therapy (NRT). The present study tested this hypothesis, using two different types of NRT medications. A secondary analysis of two randomized clinical trials was performed: One compared active 21-mg nicotine patch with placebo among 193 men and 309 women, and the other compared active 2-mg or 4-mg nicotine lozenge with placebo among 788 men and 1,030 women. Using logistic regression analysis of 6-month continuous abstinence and survival analysis, we assessed the efficacy of patch and lozenge among women and tested for a gender x treatment interaction. Active NRT was more effective than placebo among women, for both patch and lozenge. In the lozenge trial, women were less successful than men. The gender x treatment interaction was not significant in either study, whether assessed by logistic regression or survival analysis. In the lozenge trial, gender moderated the effects of smoking rate and dependence (but not treatment) on outcome: These variables affected success rates only among women. Treatment with nicotine patch or lozenge is effective for women, and the analysis did not reveal significant gender differences in efficacy. Gender differences in outcome may be moderated by nicotine dependence.

Phase III intergroup study of talc poudrage vs talc slurry sclerosis for malignant pleural effusion.

STUDY OBJECTIVE: To demonstrate the efficacy, safety, and appropriate mode of instillation of talc for sclerosis in treatment of malignant pleural effusions (MPEs). DESIGN: A prospective, randomized trial was designed to compare thoracoscopy with talc insufflation (TTI) to thoracostomy and talc slurry (TS) for patients with documented MPE. MEASUREMENTS: The primary end point was 30-day freedom from radiographic MPE recurrence among surviving patients whose lungs initially re-expanded > 90%. Morbidity, mortality, and quality of life were also assessed. RESULTS: Of 501 patients registered, those eligible were randomized to TTI (n = 242) or TS (n = 240). Patient demographics and primary malignancies were similar between study arms. Overall, there was no difference between study arms in the percentage of patients with successful 30-day outcomes (TTI, 78%; TS, 71%). However, the subgroup of patients with primary lung or breast cancer had higher success with TTI than with TS (82% vs 67%). Common morbidity included fever, dyspnea, and pain. Treatment-related mortality occurred in nine TTI patients and seven TS patients. Respiratory complications were more common following TTI than TS (14% vs 6%). Respiratory failure was observed in 4% of TS patients and 8% of TTI patients, accounting for five toxic deaths and six toxic deaths, respectively. Quality-of-life measurement demonstrated less fatigue with TTI than TS. Patient ratings of comfort and safety were also higher for TTI, but there were no differences on perceived value or convenience of the procedures. CONCLUSIONS: Both methods of talc delivery are similar in efficacy; TTI may be better for patients with either a lung or breast primary. The etiology and incidence of respiratory complications from talc need further exploration.

Successful treatment with a nicotine lozenge of smokers with prior failure in pharmacological therapy.

AIMS: To assess the influence of unsuccessful past quit attempts using pharmacological treatment on smoking cessation when using a new nicotine lozenge. DESIGN: A double-blind, randomized, placebo-controlled trial. SETTING: Fifteen sites in the United Kingdom and the United States. PARTICIPANTS: A total of 1818 smokers seeking smoking cessation treatment; 1145 had had previous pharmacological treatment for smoking cessation. INTERVENTION: Lozenge, 2 mg or 4 mg (or matched placebo); a higher dose was assigned to smokers who smoked their first cigarette of the day within 30 minutes, a sign of dependence. Smokers received minimal instruction and counseling. MEASUREMENT: Outcome was 28-day, CO-verified continuous abstinence at 6 weeks. Past use of medications was ascertained by self-report. FINDINGS: Lozenge was efficacious among smokers with prior pharmacotherapy as well as among those without such history. The effect of lozenge (versus placebo) was significantly greater among those with previous treatment experience, because previous treatment was associated with significantly poorer outcome on placebo, and active lozenge treatment corrected this imbalance. Lozenge efficacy was similar whether smokers had previously tried patch or acute forms of nicotine replacement therapy (gum, inhaler and spray), and also similar for past use of Zyban (bupriopion). CONCLUSIONS: Smokers with a history of past failure of pharmacological treatment have lower success rates without pharmacological treatment, but equally good outcomes with active lozenge treatment. Smokers who previously tried pharmacological treatments but resumed smoking should be encouraged to try quitting again with the new nicotine lozenge.

Pharmacokinetics of a nicotine polacrilex lozenge.

To evaluate the pharmacokinetic characteristics of the 2-mg and 4-mg nicotine polacrilex lozenges, the following four separate studies were conducted in healthy adult smokers: (a) A single-dose, four-way crossover (replicate design) study to compare the 4-mg lozenge and the 4-mg nicotine polacrilex gum, (b) a single-dose, two-way crossover study to compare the 2-mg lozenge and the 2-mg gum, (c) a multiple-dose, four-way crossover study to compare the lozenges administered every 90 min and the gums administered every 60 min at 2- and 4-mg dose levels, and (d) a single-dose, three-way crossover study to compare the pharmacokinetic profiles of the 4-mg lozenge when administered in three different ways: (i) Used as directed, (ii) chewed and immediately swallowed, and (iii) chewed, retained in the mouth for 5 min, and then swallowed. The single-dose studies consistently demonstrated 8%-10% higher maximal plasma concentrations and 25%-27% higher AUC values (area under the concentration-time curve) from the lozenges compared with the gums at the 2- and 4-mg dose levels, probably owing to the residual nicotine retained in the gum. The multiple-dose study applying different dosing intervals (i.e., every 90 min for the lozenges and every 60 min for the gums) resulted in approximately 30% lower AUC(0-t) values for the lozenges compared with those for the gums. Administration of the lozenge contrary to the label-specified instructions for use did not lead to a faster or higher absorption of nicotine. These pharmacokinetic characteristics should allow the lozenge to become an effective and safe therapeutic alternative for smoking cessation.