{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T20:10:33Z","timestamp":1792181433198,"version":"4.4.0"},"reference-count":35,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T00:00:00Z","timestamp":1762387200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"\n Background<\/jats:title>\n Tobacco smoking is a major global health threat. Pharmacological aids, including nicotine-replacement therapy (NRT), varenicline, and bupropion, improve quit rates but are associated with gastrointestinal (GI) adverse events (AEs) that can compromise adherence. The real-world reporting profiles of these GI AEs, particularly the differences between sexes, have not been comprehensively characterized.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n We analyzed the FDA Adverse Event Reporting System (FAERS) database from 2004 Q1 to 2024 Q2. After deduplication, reports designating NRT, varenicline, or bupropion as the primary suspect drug were extracted. Disproportionality analyses, including the Proportional Reporting Ratio (PRR) and Reporting Odds Ratio (ROR), were conducted to quantify drug-event associations. The Breslow\u2013Day test was used to assess the homogeneity of RORs between male and female strata.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Varenicline was associated with the highest proportion of GI reports (36.0% of its total reports). The disproportionality signal was significantly stronger in women than in men (ROR 6.41 vs. 5.10 for nausea,\n p<\/jats:italic>\n \u2009<\u20090.001). NRT was linked to 24.3% of GI reports, with hiccups (PRR\u2009=\u200960.1) being the most prominent signal. In contrast to varenicline, several key GI AE signals for NRT were significantly stronger in men (e.g., nausea, ROR 3.09 in men vs. 2.45 in women,\n p<\/jats:italic>\n \u2009<\u20090.001). Bupropion had the lowest proportion of GI reports (2.1%) but still generated significant disproportionality signals (overall ROR 4.50), particularly for anorexia (PRR\u2009=\u20094.80) and dry mouth (PRR\u2009=\u20094.42), with most signals being stronger in women.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n NRT, varenicline, and bupropion exhibit distinct and statistically significant sex-specific GI AE reporting profiles in a real-world setting. These hypothesis-generating findings underscore the importance of considering sex as a variable in pharmacovigilance studies and may inform future research aimed at personalizing smoking cessation therapy.<\/jats:p>\n <\/jats:sec>","DOI":"10.1371\/journal.pone.0336021","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T18:33:42Z","timestamp":1762454022000},"page":"e0336021","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Sex-stratified pharmacovigilance of gastrointestinal events associated with first-line smoking-cessation medicines: Insights from the FAERS database"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-6570-0890","authenticated-orcid":true,"given":"Haoxiong","family":"Sun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junchi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxuan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,11,6]]},"reference":[{"key":"pone.0336021.ref001","author":"WHO","year":"2023"},{"key":"pone.0336021.ref002","doi-asserted-by":"crossref","first-page":"1407741","DOI":"10.3389\/fpsyt.2024.1407741","article-title":"Exploring the relationship between smoking and poor sleep quality: a cross-sectional study using NHANES","volume":"15","author":"H Sun","year":"2024","journal-title":"Front Psych"},{"issue":"10292","key":"pone.0336021.ref003","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1016\/S0140-6736(21)01169-7","article-title":"Spatial, temporal, and demographic patterns in prevalence of smoking tobacco use and attributable disease burden in 204 countries and territories, 1990-2019: a systematic analysis from the Global Burden of Disease Study 2019","volume":"397","author":"GBD 2019 Tobacco Collaborators","year":"2021","journal-title":"Lancet"},{"issue":"5","key":"pone.0336021.ref004","article-title":"Pharmacological interventions for smoking cessation: an overview and network meta-analysis","volume":"2013","author":"K Cahill","year":"2013","journal-title":"Cochrane Database Syst Rev"},{"key":"pone.0336021.ref005","volume-title":"Smoking cessation: a report of the surgeon general","author":"USPHS","year":"2020"},{"issue":"8","key":"pone.0336021.ref006","doi-asserted-by":"crossref","DOI":"10.1136\/bmjopen-2014-005281","article-title":"Cardiovascular and neuropsychiatric safety of varenicline and bupropion compared with nicotine replacement therapy for smoking cessation: study protocol of a retrospective cohort study using the QResearch general practice database","volume":"4","author":"D Kotz","year":"2014","journal-title":"BMJ Open"},{"key":"pone.0336021.ref007","doi-asserted-by":"crossref","DOI":"10.1177\/2050312118777953","volume-title":"Adverse events of smoking cessation treatments (nicotine replacement therapy and non-nicotine prescription medication) and electronic cigarettes in the Food and Drug Administration Adverse Event Reporting System, 2004\u22122016.","author":"Y Motooka","year":"2018"},{"issue":"1","key":"pone.0336021.ref008","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/1617-9625-8-8","article-title":"Adverse events associated with nicotine replacement therapy (NRT) for smoking cessation. 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Leung","year":"2011"},{"issue":"2","key":"pone.0336021.ref012","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1177\/2045125316629071","article-title":"Bupropion: a systematic review and meta-analysis of effectiveness as an antidepressant","volume":"6","author":"K Patel","year":"2016","journal-title":"Ther Adv Psychopharmacol"},{"issue":"11","key":"pone.0336021.ref013","article-title":"Comparative effectiveness of smoking cessation medications: a national prospective cohort from Taiwan","volume":"11","author":"P-Y Chang","year":"2016","journal-title":"PLoS One"},{"key":"pone.0336021.ref014","article-title":"FDA adverse event reporting system (FAERS) essentials: a guide to understanding, applying, and interpreting adverse event data reported to FAERS","author":"E Potter","year":"2025","journal-title":"Clin Pharmacol Ther"},{"key":"pone.0336021.ref015","author":"D Administration USF a","year":"2025"},{"issue":"8","key":"pone.0336021.ref016","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1002\/pds.1001","article-title":"The reporting odds ratio and its advantages over the proportional reporting ratio","volume":"13","author":"KJ Rothman","year":"2004","journal-title":"Pharmacoepidemiol Drug Saf"},{"issue":"6","key":"pone.0336021.ref017","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1002\/pds.677","article-title":"Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports","volume":"10","author":"SJ Evans","year":"2001","journal-title":"Pharmacoepidemiol Drug Saf"},{"issue":"1","key":"pone.0336021.ref018","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/idh.12594","article-title":"Oral side effects of locally delivered nicotine replacement therapy: a meta-analysis of randomized controlled trials","volume":"21","author":"G Sivaramakrishnan","year":"2023","journal-title":"Int J Dent Hyg"},{"issue":"4","key":"pone.0336021.ref019","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1007\/s12105-021-01330-8","article-title":"Histopathologic Spectrum of Intraoral Irritant and Contact Hypersensitivity Reactions: A Series of 12 cases","volume":"15","author":"D Wang","year":"2021","journal-title":"Head Neck Pathol"},{"key":"pone.0336021.ref020","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1016\/S0016-5085(19)31778-0","article-title":"Simultaneous measurement of basal pancreatic, gastric acid secretion, plasma gastrin, and secretin during smoking","volume":"73","author":"SN Murthy","year":"1977","journal-title":"Gastroenterology"},{"issue":"2","key":"pone.0336021.ref021","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1111\/j.1365-2036.1988.tb00685.x","article-title":"The effect of nicotine on the delay of gastric emptying","volume":"2","author":"ER Gritz","year":"1988","journal-title":"Aliment Pharmacol 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Watson","year":"2019","journal-title":"EClinicalMedicine"},{"issue":"2","key":"pone.0336021.ref031","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1037\/1064-1297.7.2.135","article-title":"Gender differences in response to nicotine replacement therapy: objective and subjective indexes of tobacco withdrawal","volume":"7","author":"DW Wetter","year":"1999","journal-title":"Exp Clin Psychopharmacol"},{"key":"pone.0336021.ref032","doi-asserted-by":"crossref","DOI":"10.18332\/tpc\/194629","article-title":"Use of low-dose varenicline in patients who do not tolerate standard-dose varenicline: A longitudinal case series","volume":"11","author":"M Swanson","year":"2025","journal-title":"Tob Prev Cessat"},{"key":"pone.0336021.ref033","doi-asserted-by":"crossref","first-page":"110266","DOI":"10.1016\/j.pnpbp.2021.110266","article-title":"Gastrointestinal side effects associated with antidepressant treatments in patients with major depressive disorder: A systematic review and 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