Pilot randomized controlled trial evaluating the effect of random nicotine delivery on cigarettes per day and smoke exposure.

BACKGROUND: Many smokers report attempting to quit each year, yet most relapse, in part due to exposure to smoking-related cues. It is hypothesized that extinction of the cue-drug association could be facilitated through random nicotine delivery (RND), thus making it easier for smokers to quit. The current study aimed to evaluate the effects of RND on smoking cessation-related outcomes including cigarettes per day (CPD) and exhaled carbon monoxide (CO). METHODS: Participants were current smokers (>9 CPD) interested in quitting. Novel trans-mucosal, orally dissolving nicotine films, developed by Bionex Pharmaceuticals, were used in the study. The pharmacokinetic profile of these films was assessed in single (Experiment 1) and multiple-dose (Experiment 2) administrations prior to the smoking cessation study (Experiment 3). In Experiment 3, participants were randomized 1:1:1 to recieve 4 nicotine films per day of either: placebo delivery (0 mg), steady-state delivery (2 mg), or random nicotine delivery (RND) (0 mg or 4 mg). After two weeks, participants were advised to quit (target quit date, TQD) and were followed up 4 weeks later to collect CPD and CO and to measure dependence (Penn State Cigarette Dependence Index; PSCDI) and craving (Questionnaire of Smoking Urges; QSU-Brief). Means and frequencies were used to describe the data and repeated measures ANOVA was used to determine differences between groups. RESULTS: The pharmacokinetic studies (Experiment 1 and 2) demonstrated that the films designed for this study delivered nicotine as expected, with the 4 mg film delivering a nicotine boost of approximately 12.4 ng/mL across both the single and the multiple dose administration studies. The films reduced craving for a cigarette and were well-tolerated, overall, and caused no changes in blood pressure or heart rate. Using these films in the cessation study (Experiment 3) (n = 45), there was a significant overall reduction in cigarettes smoked per day (CPD) and in exhaled CO, with no significant differences across groups (placebo, steady-state, RND). In addition, there were no group differences in dependence or craving. Adverse events included heartburn, hiccups, nausea, and to a lesser extent, vomiting and anxiety and there were no differences across groups. CONCLUSION: Overall, this pilot study found that RND via orally dissolving films was feasible and well tolerated by participants. However, RND participants did not experience a greater reduction in self-reported CPD and exhaled CO, compared with participants in the steady-state and placebo delivery groups. Future studies to evaluate optimal RND parameters with larger sample sizes are needed to fully understand the effect of RND on smoking cessation-related outcomes.

Adjunctive osteopathic therapy for hospitalized COVID-19 patients: A feasibility-oriented chart review study with matched controls.

Background: Osteopathic manipulative treatment (OMT) may improve outcomes during COVID-related respiratory distress - the most common cause of death from novel coronavirus (SARS-CoV-2). Outcomes from OMT treatments of respiratory distress during the COVID-19 pandemic have not been reported. Objective: Assess adjunctive OMT in hospitalized patients with SARS-CoV-2 and respiratory distress. Design: Feasibility oriented retrospective observational cohort study. Setting: COVID-19 (non-ICU) ward in a tertiary academic medical center. Methods: Inpatients received daily OMT treatments of rib raising, abdominal diaphragm doming, thoracic pump and pedal pump. Primary outcomes were procedural acceptance, satisfaction, side effects, and adverse events. Secondary outcomes were patient-reported clinical change after therapy; number of hospital days; need during hospitalization for high-flow oxygen, C-PAP/BiPAP or intensive care; need for supplementary oxygen at discharge; and discharge disposition. Participants: Hospitalized adults with SARS-CoV-2 infection and respiratory distress. Results: OMT (n = 27) and Control (n = 152) groups were similar in demographics and most laboratory studies. 90% of patients accepted OMT and reported high satisfaction (4.26/±0.71 (maximum 5)), few negative effects, no adverse events, and positive clinical change (5.07 ± 0.96 (maximum 7)). Although no significant differences were found in secondary outcomes, OMT patients trended towards fewer hospital days than Controls (p = 0.053; Cohen's d = 0.22), a relationship that trended towards correlation with number of co-morbidities (p = 0.068). Conclusion: Hospitalized patients with respiratory distress and COVID-19 reported acceptance, satisfaction, and greater ease of breathing after a four-part OMT protocol, and appear to have a shorter length of hospitalization. Randomized controlled trials are needed to confirm these results.

Intentions and Attempts to Quit JUUL E-Cigarette Use: The Role of Perceived Harm and Addiction.

INTRODUCTION: Research on electronic cigarette (e-cigarette) quit intentions and attempts is limited despite the potential health benefits of quitting, especially for long-term users. The current study aimed to investigate perceptions of harm and addictiveness and tobacco use characteristics associated with quit variables among users of a popular e-cigarette brand, JUUL. METHODS: We surveyed 301 US adult JUUL users on their tobacco use characteristics, perceptions of JUUL harm and addictiveness, and quit variables at 3 time points, from July 2019 to April 2020. We used logistic regression models to assess demographic characteristics, smoking characteristics, and perceptions of JUUL harm and addictiveness as correlates of e-cigarette quit intentions, attempts, importance, and confidence. RESULTS: Twenty-three percent of the sample had intentions to quit using JUUL within the year, and 22.6% reported making a lifetime quit attempt. The average rating of quit importance was 4.1 and quit confidence was 5.8 on a Likert scale of 1 to 10. More than 90% of the sample indicated that JUUL was at least moderately addictive, whereas less than one-quarter indicated that JUUL was as harmful or more harmful than smoking. Higher levels of perceived JUUL addictiveness were associated with more quit intentions, attempts, and importance. Higher levels of perceived JUUL harm compared with smoking were associated with more quit importance. CONCLUSION: Our findings suggest that a small proportion of adult JUUL users are interested in quitting. Self-reported perceptions of JUUL's addiction potential may be related to more quit attempts. Findings highlight the need for evidence-based information on e-cigarette addictiveness and effective strategies for cessation.

Switching to Progressively Reduced Nicotine Content Cigarettes in Smokers With Low Socioeconomic Status: A Double-Blind Randomized Clinical Trial.

INTRODUCTION: The Food and Drug Administration issued an advanced notice of proposed rulemaking for setting a product standard for nicotine levels in cigarettes, with an emphasis on minimally or non-addicting very low nicotine content (VLNC). METHODS: A 33 week, two-arm, double-blind randomized trial conducted in Hershey, Pennsylvania, USA and Washington, DC, USA included adult daily cigarette smokers (≥5 cigarettes per day) with less than a college degree, and who had no plans to quit within the next six months. Participants were randomized to either reduced nicotine content (RNC) study cigarettes tapered every three weeks to a final VLNC (0.2 mg/cigarette) for six weeks or to usual nicotine content (UNC) study cigarettes (11.6 mg/cigarette). Outcomes included acceptability of study cigarettes measured by attrition (primary outcome), compliance, reduction in cigarette dependence and tobacco biomarkers, and post-intervention cessation. RESULTS: The RNC (n = 122) versus UNC (n = 123) group had higher attrition (adjusted Hazard Ratio 3.4; 95% confidence interval [CI] 1.99 to 5.81). At the end of the intervention, cotinine levels were 50% lower in the RNC group (mean group difference -137 ng/mL; 95% CI -172, -102). The RNC group smoked fewer CPD (-4.1; 95% CI -6.44, -1.75) and had lower carbon monoxide levels (-4.0 ppm; 95% CI -7.7, -0.4). Forty seven percent (29/62) of the RNC group were biochemically-confirmed compliant with smoking VLNC cigarettes (mean cotinine = 8.9 ng/ml). At three month follow-up, only compliant VLNC smokers quit with an assisted quit attempt (N = 6/22, 27%). CONCLUSIONS: This study supports a VLNC standard in cigarettes. IMPLICATIONS: Differential dropout and noncompliance indicate some smokers had difficulty transitioning to cigarettes with reduced nicotine. These smokers will benefit from supplemental nicotine in medicinal or noncombustible tobacco products if a nicotine reduction standard is established. Other smokers successfully transitioned to very low nicotine content cigarettes exclusively and substantially reduced their exposure to nicotine.

An Electronic Aerosol Delivery System for Functional Magnetic Resonance Imaging.

BACKGROUND: Public health concerns over the addictive potential of electronic cigarettes (e-cigs) have heightened in recent years. Brain function during e-cig use could provide an objective measure of the addictive potential of new vaping products to facilitate research; however, there are limited methods for delivering e-cig aerosols during functional magnetic resonance imaging (fMRI). The current study describes the development and feasibility testing of a prototype to deliver up to four different e-cig aerosols during fMRI. METHODS: Standardized methods were used to test the devices' air flow variability, nicotine yield, and free radical production. MRI scans were run with and without the device present to assess its safety and effects on MRI data quality. Five daily smokers were recruited to assess plasma nicotine absorption from e-liquids containing nicotine concentrations of 8, 11, 16, 24, and 36 mg/ml. Feedback was collected from participants through a semi-structured interview and computerized questionnaire to assess comfort and subjective experiences of inhaling aerosol from the device. RESULTS: Nicotine yield captured from the aerosol produced by the device was highly correlated with the nicotine concentration of the e-liquids used (R2 = 0.965). Nicotine yield was reduced by a mean of 48% and free radical production by 17% after traveling through the device. The e-liquid containing the highest nicotine concentration tested (36 mg/ml) resulted in the highest plasma nicotine boost (6.6 ng/ml). Overall, participants reported that the device was comfortable to use and inhaling the e-cig aerosols was tolerable. The device was determined to be safe for use during fMRI and had insignificant effects on scan quality. CONCLUSIONS: With the current project, we were able to design a working prototype that safely and effectively delivers e-cig aerosols during fMRI. The device has the potential to be used to assess brain activation during e-cig use and to compare brain reactivity to varying flavors, nicotine concentrations, and other e-cig characteristics.

Response to Flavored Cartridge/Pod-Based Product Ban among Adult JUUL Users: "You Get Nicotine However You Can Get It".

In order to curb increasing youth electronic cigarette (e-cig) use, the United States Food and Drug Administration (FDA) banned the sale of flavored cartridge/pod-based products in February 2020. This mixed-methods study aimed to evaluate the impact of the FDA ban on adult JUUL users. The samples of current adult JUUL users were surveyed via Amazon Mechanical Turk at three time-points n = 76 (Sample 1); n = 128 (Sample 2); n = 86 (Sample 3) before and after the FDA flavored/pod ban. The participants were asked to report the JUUL flavored pod used most often and answer questions on purchasing generic pods or refilling (Quantitative). JUUL users were then interviewed in order to explore their perceptions and behaviors related to the FDA ban of flavored cartridge/pod-based products (Qualitative; n = 16). Quantitative data analysis evaluated the differences in variables by time-point. Qualitative data were coded into themes while using the constant comparative method. We found a significant decrease in the use of mint pods (43.4%, 22.7%, 16.3%) (p < 0.01), while there was a significant increase in the use of menthol pods (6.6%, 26.6%, 37.2%) (p < 0.01). Themes that emerged from the qualitative data included switching from mint to menthol pods, refilling pods, and switching to other products that are available in the desired flavors, such as generic pods or disposable e-cigs. Future research is needed in order to evaluate the impact of these behaviors on public health.

Correction to Reduced nicotine content cigarettes in smokers of low socioeconomic status: study protocol for a randomized control trial.

CORRECTION: The title of the original publication [1] had an error; furthermore there were errors in Fig. 2. The corrected version of the title and of Fig. 2 can be found below in this Erratum.

Reduced nicotine content cigarettes in smokers of low socioeconomic status: study protocol for a randomized control trial.

BACKGROUND: The Family Smoking Prevention and Tobacco Control Act gave the Food and Drug Administration jurisdiction over the regulation of all tobacco products, including their nicotine content. Under this act, a major strategy to reduce harm from cigarette tobacco is lowering the nicotine content without causing unintended adverse consequences. Initial research on reduced nicotine content (RNC) cigarettes has shown that smokers of these cigarettes gradually decrease their smoking frequency and biomarkers of exposure. The effectiveness of this strategy needs to be demonstrated in different populations whose response to RNC cigarettes might be substantially mediated by personal or environmental factors, such as low socioeconomic status (SES) populations. This study aims to evaluate the response to a reduced nicotine intervention in low SES smokers, as defined here as those with less than 16 years of education, by switching smokers from high nicotine commercial cigarettes to RNC cigarettes. METHODS/DESIGN: Adults (N = 280) who have smoked five cigarettes or more per day for the past year, have not made a quit attempt in the prior month, are not planning to quit, and have less than 16 years of education are recruited into a two-arm, double-blinded randomized controlled trial. First, participants smoke their usual brand of cigarettes for 1 week and SPECTRUM research cigarettes containing a usual amount of nicotine for 2 weeks. During the experimental phase, participants are randomized to continue smoking SPECTRUM research cigarettes that contain either (1) usual nicotine content (UNC) (11.6 mg/cigarette) or (2) RNC (11.6 to 0.2 mg/cigarette) over 18 weeks. During the final phase of the study, all participants are offered the choice to quit smoking with nicotine replacement therapy, continue smoking the research cigarettes, or return to their usual brand of cigarettes. The primary outcomes of the study include retention rates and compliance with using only research cigarettes and no use of other nicotine-containing products. Secondary outcomes are tobacco smoke biomarkers, nicotine dependence measures, smoking topography, stress levels, and adverse health consequences. DISCUSSION: Results from this study will provide information on whether low SES smokers can maintain a course of progressive nicotine reduction without increases in incidence of adverse effects. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01928719 . Registered on 21 August 2013.

The nicotine dependence phenotype, time to first cigarette, and larynx cancer risk.

PURPOSE: Cigarette smoking is the major cause of laryngeal cancer. The time to first cigarette after waking in the morning is a behavior associated with several dimensions of nicotine dependence including the dose of smoke uptake. We hypothesized that a short TTFC increases the risk of laryngeal cancer. METHODS: The analysis was based on data from a hospital-based case-control study of laryngeal cancer. The current analysis included only subjects who were ever cigarette smokers, including 570 cases and 343 controls (832 whites and 81 blacks). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression adjusting for smoking history and other potential confounders. Incidence data from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute from 1975 to 2006 were analyzed for trends in laryngeal cancer. RESULTS: There was a dose-response relationship between TTFC and supraglottic cancer. Compared to subjects who smoked more than 60 min after waking, the adjusted odds ratio was 1.51 (95% CI, 0.63-3.61) for 30-60 min and 3.13 (95% CI, 1.56-6.30) for 0-30 min. No association was observed between TTFC and cancer of the glottis. In blacks, the TTFC was not associated with the risk of laryngeal cancer. Trends in SEER rates were similar for cancer of the glottis and supraglottis, indicating that the site-specific differences were not affected by unknown confounders. CONCLUSION: A nicotine dependence behavior that is associated with cigarette smoke uptake increases the risk of cancer of the supraglottis larynx, but not glottis larynx.