Nicotine gum and transdermal nicotine have been shown to relieve withdrawal and double success rates over placebo in trials of smoking cessation. This study tested whether combining the two methods would relieve withdrawal more effectively compared to either treatment alone. Twenty-eight smokers served as their own controls in each of four conditions: active gum + active patch (double active), active gum + placebo patch (gum only active), placebo gum + active patch (patch active) and placebo gum + placebo patch (double placebo). This "double placebo" design controls sensory, psychological and ritual variables associated with each drug form. Withdrawal symptoms were rated four times daily for 3 days in each condition. Total baseline (smoking) withdrawal scores using visual analogue scales (VAS) averaged 101.1. During cessation, total withdrawal increased to 187.0 for the double placebo condition, 142.2 for the active gum/placebo patch treatment and 128.3 for the active patch/placebo gum treatment. The double active condition equalled smoking with score 99.2. All pairwise comparisons were significant (P < 0.001) except between the two single active conditions and between smoking versus the double active condition. Significant time-of-day effects by treatment on withdrawal were observed for the double placebo condition (P < 0.05) with less withdrawal in the morning. The findings suggest: 1) combining nicotine gum with transdermal nicotine may be superior to either treatment alone, 2) more symptoms may be nicotine specific (relieved by replacement) than previously thought.

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The single dose pharmacokinetics of a novel, non-tobacco-based nicotine pouch, ZYN®, 3 and 6 mg, were compared to 8 mg General snus (Part 1) and ZYN® 8 mg was compared to 18 mg Longhorn moist snuff (Part 2). Methods A single-dose randomized cross-over design was used. In-vivo extraction and pharmacokinetic parameters were determined. Results Part1. The AUCinf of ZYN® 3mg was 27% smaller than that of 8mg General and the AUCinf of ZYN® 6 mg was 34% larger than that of 8mg General. Less nicotine was extracted from ZYN® 3 mg (1.5 mg) and more from ZYN® 6 mg (3.5 mg)than from 8mg General (2.4 mg). The extracted fractions of nicotine for both ZYN® products (56% and 59%) were significantly larger than for 8mg General (32%). Results Part 2. Close to identical plasma nicotine curves, AUCinf and Cmax were found for ZYN® 8 mg and Longhorn Natural 18 mg moist snuff. The extracted amount of nicotine from ZYN® 8 mg (3.8 mg) was larger than the amount extracted from Longhorn Natural 18 mg (3.0 mg, but smaller than the extracted amount of nicotine from General 2x8 mg snus pouches (5.0 mg). The extracted fraction of nicotine for ZYN® 8 mg (50%) was larger than for Longhorn Natural (19%) and General 2x8mg snus pouches (33%). Conclusions The two higher doses of ZYN (6 mg and 8 mg) deliver nicotine as quickly and to a similar extent as existing smokeless products, with no significant adverse effects. Implications The present study demonstrates the characteristics of three strengths of a novel tobacco-free oral snus, ZYN®, viz. the extraction of nicotine from the oral cavity and its uptake into the systemic blood circulation. Comparison is made to Swedish General® snus and American Longhorn® moist snuff and from literature 4 mg Nicorette® gum and 13 brands of e-cigarettes.

The present study evaluated nicotine plasma levels achieved following 1 day's regular use of four commonly used brands of Swedish portion snus and 2-mg Nicorette chewing gum. The study also estimated the amount of sodium chloride extracted from each snus sachet to identify potential risks for exacerbation of heart failure and hypertension with the use of Swedish snus. Extracted dose of nicotine, area under the venous plasma concentration-time curve (AUC), maximum plasma nicotine concentration (Cmax) of the last (12th) dosing interval, and the Cmax and AUC ratios versus Nicorette were calculated. Relative bioavailable dose was calculated using AUC of 2-mg Nicorette gum as the reference. The mean extracted nicotine doses were 2.74+/-0.80, 1.55+/-0.68, 2.00+/-0.56, and 1.08+/-0.94 mg/sachet for General, Catch Licorice, Catch Mini, and Catch Dry Mini snus, respectively. The approximate bioavailable dose of nicotine from snus was 40%-60% of the extracted dose. The steady-state nicotine plasma concentration-time curve for the weakest brand, Catch Dry Mini portion snus, did not differ significantly from that of the 2-mg Nicorette gum. The AUC and Cmax for Catch Licorice 1 g and Catch Mini 0.5 g portion snus were twice those for the 2-mg Nicorette gum; for the strongest brand, General, these values were 2(1/2) times those for Nicorette gum. The differences in AUC and Cmax versus the 2-mg Nicorette gum were statistically significant (p=.020). Nicotine plasma levels with General portion snus were sustained at higher levels than current nicotine replacement therapy products, peaking at 29.0+/-8.5 ng/ml, and more closely mimicking cigarette smokers' nicotine plasma levels. The risks of aggravation of heart failure and hypertension with respect to increased salt load from the use of snus appeared to be negligible.

Nicotine absorption after use of the vapour inhaler occurs primarily via the mucosa of the oral cavity; the absorption occurs slowly and the arterial nicotine concentration spike, typical of cigarette smoking, is avoided. Thus, the likelihood for abuse of the nicotine inhaler is probably small.