Oral nicotine pouches for cessation or reduction of use of other tobacco or nicotine products.

RATIONALE: Oral nicotine pouches (ONP) emerged in the late 2000s, but have gained popularity since their introduction to the global market in 2016, with claims about their harm reduction potential. OBJECTIVES: Primary objectives • To evaluate the benefits and harms of ONP when used to help people transition away from combustible tobacco use (smoking). • To evaluate the impact of ONP on the prevalence of combustible tobacco use. Secondary objectives • To evaluate the benefits and harms of ONP when used to help people transition away from other non-combustible tobacco/commercial nicotine product use. • To evaluate the impact of ONP on the prevalence of use of other non-combustible tobacco/commercial nicotine products. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and PsycINFO from 2000 to 13 January 2025. We also covered ClinicalTrials.gov and the WHO ICTRP through our search of CENTRAL. ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) of ONP in people using tobacco or other non-combustible tobacco/non-pharmaceutical nicotine products. RCTs must have reported tobacco/nicotine use at 4+ weeks or biomarkers or adverse events at 1+ weeks. We also sought interrupted/multiple time-series studies of ONP's population-level effects on the prevalence of use of other tobacco/nicotine products. OUTCOMES: Our critical outcomes were: smoking abstinence at 4+ weeks; number of people reporting serious adverse events (SAEs) at 1+ weeks; and change in the prevalence of smoking. Important outcomes included tobacco-specific nitrosamines (TSNAs), carboxyhaemoglobin (COHb), metals, and inflammatory markers detected in human biosamples. RISK OF BIAS: We used the Cochrane RoB 1 tool to assess risk of bias. SYNTHESIS METHODS: We synthesised results using random-effects meta-analysis where possible. We used I2 to quantify statistical heterogeneity. Where meta-analysis was not possible, we graphically plotted available data in forest plots. We used risk ratios (RR) for dichotomous outcomes and mean differences (MD) or standardised mean differences (SMD) for continuous outcomes, with 95% confidence intervals (CI). We assessed the certainty of evidence using GRADE. INCLUDED STUDIES: We included four small studies (n < 150 for each, total n = 284; 3 independent, 1 industry-funded; 3 at high risk of bias and 1 at unclear risk of bias). All were RCTs in people who smoked combustible cigarettes at baseline. Three were conducted in the USA, and one in New Zealand. Two compared higher- versus lower-nicotine dose ONP. Two compared ONP to instructions to continue smoking as usual. One each compared ONP to electronic cigarettes (e-cigarettes), snus, and pharmaceutical nicotine replacement therapy (NRT). SYNTHESIS OF RESULTS: Smoking abstinence Smoking abstinence may be slightly higher in people randomised to ONP compared to no intervention at eight-week follow-up (RR 1.58, 95% CI 0.07 to 35.32; 1 study, 27 participants; very low-certainty evidence (risk of bias and imprecision; CI incorporated possibility of no difference)), but the evidence is very uncertain. Low-certainty evidence (serious imprecision; CI incorporated possibility of no difference) suggests there may be lower abstinence rates in those randomised to ONP compared to e-cigarettes (RR 0.25, 95% CI 0.03 to 2.02; 1 study, 36 participants). Evidence from one study (n = 30) comparing higher- versus lower-dose ONP found a higher quit rate in the higher-dose arm, but again with wide CI encompassing the possibility of no difference and of higher quit rates in the lower-dose arm (RR 5.00, 95% CI 0.26 to 96.13; evidence certainty not assessed). Serious adverse events No SAEs occurred in the three studies reporting this outcome. Data were available for the comparisons ONP versus minimal control (2 studies, 124 participants; very low-certainty evidence (risk of bias and serious imprecision)) and ONP versus e-cigarettes (1 study, 26 participants; low-certainty evidence (serious imprecision)). TSNA One study reported on a TSNA (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL)) comparing ONP with instructions to continue smoking. There may be lower levels with ONP (MD -265.30 ng/g creatinine, 95% CI -350.64 to -179.96; 53 participants; very low-certainty evidence (risk of bias and imprecision)), but the evidence is very uncertain. Data from two studies suggested no difference in NNAL levels between higher- and lower-dose ONP (SMD -0.16, 95% CI -1.87 to 1.56; I2 = 0%; 77 participants; evidence certainty not assessed). COHb Based on one study, there may be lower levels of COHb with ONP compared to instructions to continue smoking (MD -6.7%, 95% CI -8.33 to -5.07; 53 participants; very low-certainty evidence (risk of bias and imprecision)), but the evidence is very uncertain. When comparing higher- versus lower-dose ONP, the same study found very slightly lower levels in the higher-dose group, with the 95% CI incorporating the possibility of no difference (MD -0.40%, 95% CI -1.19 to 0.39; evidence certainty not assessed). No studies reported on prevalence, inflammatory markers, metals, or use of tobacco/nicotine products other than cigarettes. AUTHORS' CONCLUSIONS: There is limited evidence on the use of ONP for cessation or reduction of cigarette use. There is no evidence on the use of ONP for cessation or reduction of other tobacco or nicotine products or on the effects of ONP on prevalence of tobacco use/nicotine vaping. Low-certainty evidence suggests that people randomised to ONP may be slightly less likely to quit smoking than those randomised to e-cigarettes, but data were from one small study and therefore imprecise. Limited, short-term data did not identify any serious health harms from ONP when used to help people transition away from tobacco smoking. More research on the effects of ONP for cessation or reduction of use of other tobacco or non-pharmaceutical nicotine products is urgently needed. Future trials should prioritise comparing ONP to other active interventions (e.g. NRT and e-cigarettes). FUNDING: This Cochrane review was funded by the National Cancer Institute of the National Institutes of Health (NIH) and FDA Center for Tobacco Products (CTP) under Award Number 2U54CA229974. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the Food & Drug Administration. REGISTRATION: Registration: Cochrane, via protocol available via DOI:10.1002/14651858.CD016220.