{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T16:16:25Z","timestamp":1782922585807,"version":"3.54.5"},"reference-count":46,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,24]],"date-time":"2021-12-24T00:00:00Z","timestamp":1640304000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japanese Society for Pharmaceutical Palliative Care and Sciences","award":["202102"],"award-info":[{"award-number":["202102"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>In this study, we used the large number of cases in the FDA adverse-event reporting system (FAERS) database to investigate risk factors for drug-induced hiccups and to explore the relationship between hiccups and gender. From 11,810,863 adverse drug reactions reported between the first quarter of 2004 and the first quarter of 2020, we extracted only those in which side effects occurred between the beginning and end of drug administration. Our sample included 1454 adverse reactions for hiccups, with 1159 involving males and 257 involving females (the gender in 38 reports was unknown). We performed univariate analyses of the presence or absence of hiccups for each drug and performed multivariate analysis by adding patient information. The multivariate analysis showed nicotine products to be key suspect drugs for both men and women. For males, the risk factors for hiccups included older age, lower body weight, nicotine, and 14 other drugs. For females, only nicotine and three other drugs were extracted as independent risk factors. Using FAERS, we were thus able to extract new suspect drugs for drug-induced hiccups. Furthermore, this is the first report of a gender-specific analysis of risk factors for hiccups that provides novel insights into drug-induced hiccups, and it suggests that the mechanism responsible is strongly related to gender. Thus, this study can contribute to elucidating the mechanism underlying this phenomenon.<\/jats:p>","DOI":"10.3390\/ph15010027","type":"journal-article","created":{"date-parts":[[2021,12,27]],"date-time":"2021-12-27T01:06:54Z","timestamp":1640567214000},"page":"27","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Analysis of Factors Associated with Hiccups Using the FAERS Database"],"prefix":"10.3390","volume":"15","author":[{"given":"Ryuichiro","family":"Hosoya","sequence":"first","affiliation":[{"name":"Department of Medical Molecular Informatics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan"},{"name":"Department of Pharmacy, Japanese Red Cross Musashino Hospital, 1-26-1 Kyonan-cho, Musashino, Tokyo 180-8610, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reiko","family":"Ishii-Nozawa","sequence":"additional","affiliation":[{"name":"Department of Clinical Neuropharmacology, Education and Research Unit for Comprehensive Clinical Pharmacy, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kota","family":"Kurosaki","sequence":"additional","affiliation":[{"name":"Department of Medical Molecular Informatics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5773-991X","authenticated-orcid":false,"given":"Yoshihiro","family":"Uesawa","sequence":"additional","affiliation":[{"name":"Department of Medical Molecular Informatics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"150","DOI":"10.2344\/0003-3006-57.4.150","article-title":"Nausea, Vomiting, and Hiccups: A Review of Mechanisms and Treatment","volume":"57","author":"Becker","year":"2010","journal-title":"Anesth. Prog."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/S0196-0644(05)81620-8","article-title":"Hiccups (singultus): Review and approach to management","volume":"20","author":"Kolodzik","year":"1991","journal-title":"Ann. Emerg. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/S0168-0102(03)00225-6","article-title":"Hiccup reflex is mediated by pharyngeal branch of glossopharyngeal nerve in cats","volume":"47","author":"Kondo","year":"2003","journal-title":"Neurosci. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/S0168-0102(98)00011-X","article-title":"GABAergic inhibition of hiccup-like reflex induced by electrical stimulation in medulla of cats","volume":"30","author":"Oshima","year":"1998","journal-title":"Neurosci. Res."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Nausheen, F., Mohsin, H., and Lakhan, S.E. (2016). Neurotransmitters in Hiccups, SpringerOpen.","DOI":"10.1186\/s40064-016-3034-3"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.jpainsymman.2015.09.013","article-title":"Gender Differences in Hiccup Patients: Analysis of Published Case Reports and Case-Control Studies","volume":"51","author":"Lee","year":"2016","journal-title":"J. Pain Symptom Manag."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1177\/0897190014544797","article-title":"Aripiprazole-associated hiccups: A case and closer look at the association between hiccups and antipsychotics","volume":"27","author":"Silverman","year":"2014","journal-title":"J. Pharm. Pract."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"89","DOI":"10.5649\/jjphcs.35.89","article-title":"Study on Risk Factors for Hiccups Induced by Cisplatin-based Chemotherapy","volume":"35","author":"Hayashi","year":"2009","journal-title":"Jpn. J. Pharm. Health Care Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"124","DOI":"10.4236\/pp.2018.94010","article-title":"Effect of Antiemetic Agents on Hiccups during Chemotherapy in Patients with Lung Cancer","volume":"9","author":"Toriumi","year":"2018","journal-title":"Pharmacol. Pharm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1634\/theoncologist.2013-0224","article-title":"Treatment of Dexamethasone-Induced Hiccup in Chemotherapy Patients by Methylprednisolone Rotation","volume":"18","author":"Lee","year":"2013","journal-title":"Oncologist"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Hosoya, R., Uesawa, Y., Ishii-Nozawa, R., and Kagaya, H. (2017). Analysis of factors associated with hiccups based on the Japanese Adverse Drug Event Report database. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0172057"},{"key":"ref_12","first-page":"167","article-title":"Demographic and clinical risk factors of hiccups","volume":"3","author":"Hosoya","year":"2018","journal-title":"J. Pharm. Pharmacol. Sci. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"331","DOI":"10.4236\/pp.2018.98026","article-title":"Risk Factors for Cancer Chemotherapy-Induced Hiccups (CIH)","volume":"9","author":"Hosoya","year":"2018","journal-title":"Pharmacol. Pharm."},{"key":"ref_14","unstructured":"(2021, November 04). FDA FAERS, Available online: https:\/\/www.fda.gov\/drugs\/questions-and-answers-fdas-adverse-event-reporting-system-faers\/fda-adverse-event-reporting-system-faers-public-dashboard."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"629","DOI":"10.3389\/fnins.2020.00629","article-title":"The Role of Serotonin in Singultus: A Review","volume":"14","author":"Petroianu","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1113\/JP279942","article-title":"Sexually dimorphic response of colorectal motility to noxious stimuli in the colorectum in rats","volume":"599","author":"Horii","year":"2021","journal-title":"J. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e27","DOI":"10.1016\/j.annfar.2013.10.023","article-title":"Baclofen for the treatment of hiccup related to brainstem compression","volume":"33","author":"Baumann","year":"2014","journal-title":"Ann. Fr. d\u2019Anesth\u00e9sie R\u00e9anim."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1113\/jphysiol.2004.062471","article-title":"Cl\u2212 uptake promoting depolarizing GABA actions in immature rat neocortical neurones is mediated by NKCC1","volume":"557","author":"Yamada","year":"2004","journal-title":"J. Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1177\/106002809703101025","article-title":"Hiccups following nicotine gum use","volume":"31","author":"Einarson","year":"1997","journal-title":"Ann. Pharmacother."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/0163-7258(82)90058-4","article-title":"The effects of nicotine on brain neurotransmitter systems","volume":"16","author":"Balfour","year":"1982","journal-title":"Pharmacol. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1016\/0028-3908(74)90093-8","article-title":"Effects of nicotine on distribution and release of 14C-norepinephrine and 14C-dopamine in rat brain striatum and hypothalamus slices","volume":"13","author":"Goodman","year":"1974","journal-title":"Neuropharmacology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1136\/bmjspcare-2016-001264","article-title":"Management of hiccups in palliative care patients","volume":"8","author":"Jeon","year":"2017","journal-title":"BMJ Support. Palliat. Care"},{"key":"ref_23","first-page":"203","article-title":"EMESIS AND HICCOUGH\u2014Treatment with Chlorpromazine","volume":"81","author":"Stewart","year":"1954","journal-title":"Calif. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"87","DOI":"10.2974\/kmj.48.87","article-title":"Profiles of Affinity of Antipsychotic Drug for Neurotransmitter Receptors and Their Clinical Inplication","volume":"48","author":"Yonemura","year":"1998","journal-title":"Kitakanto Med. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1002\/mds.22395","article-title":"Hiccups associated with levodopa in Parkinson\u2019s disease","volume":"24","author":"Gerschlager","year":"2009","journal-title":"Mov. Disord."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1176\/appi.neuropsych.13100307","article-title":"Aripiprazole-Induced Acute Hiccups: A Case Report","volume":"27","author":"Kani","year":"2015","journal-title":"J. Neuropsychiatry Clin. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1097\/WNF.0000000000000032","article-title":"Hiccups Associated With Switching From Olanzapine to Aripiprazole in a Patient with Paranoid Schizophrenia","volume":"37","author":"Hori","year":"2014","journal-title":"Clin. Neuropharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1016\/j.genhosppsych.2008.09.014","article-title":"Aripiprazole-induced hiccups: A case report","volume":"31","author":"Ray","year":"2009","journal-title":"Gen. Hosp. Psychiatry"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"247","DOI":"10.31083\/j.jin.2021.01.273","article-title":"The action of aripiprazole and brexpiprazole at the receptor level in singultus","volume":"20","author":"Alefishat","year":"2021","journal-title":"J. Integr. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1097\/WNF.0000000000000311","article-title":"Possible Sertraline-Induced Hiccups in a Boy with Obsessive-Compulsive Disorder and Attention-Deficit\/Hyperactivity Disorder","volume":"42","year":"2019","journal-title":"Clin. Neuropharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1176\/appi.psy.41.4.353","article-title":"Sertraline in the Treatment of Hiccups","volume":"41","author":"Vaidya","year":"2000","journal-title":"J. Psychosom. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/S0006-3223(01)01145-3","article-title":"Second-generation SSRIs: Human monoamine transporter binding profile of escitalopram and R-fluoxetine","volume":"50","author":"Owens","year":"2001","journal-title":"Biol. Psychiatry"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1038\/sj.bjc.6603048","article-title":"Side effects associated with the use of dexamethasone for prophylaxis of delayed emesis after moderately emetogenic chemotherapy","volume":"94","author":"Vardy","year":"2006","journal-title":"Br. J. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.ejphar.2013.10.008","article-title":"The cellular mechanisms of the antiemetic action of dexamethasone and related glucocorticoids against vomiting","volume":"722","author":"Chu","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_35","first-page":"115","article-title":"Three cases of drug-induced hiccup: Causative drugs and mechanisms\u2013The relationship with GABA receptor action","volume":"30","author":"Kondo","year":"2019","journal-title":"J. Jpn. Assoc. Acute Med."},{"key":"ref_36","unstructured":"Popoli, M., Yan, Z., Mcewen, B.S., and Sanacora, G. (2021, November 04). The Stressed Synapse: The Impact of Stress and Glucocorticoids on Glutamate Transmission, Available online: https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3645314\/."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.jpainsymman.2005.08.008","article-title":"Cisplatin-Related Hiccups: Male Predominance, Induction by Dexamethasone, and Protection against Nausea and Vomiting","volume":"30","author":"Liaw","year":"2005","journal-title":"J. Pain Symptom Manag."},{"key":"ref_38","first-page":"1008","article-title":"Control of chemotherapy-induced emesis","volume":"329","author":"Grunberg","year":"1993","journal-title":"N. Engl. J. Med."},{"key":"ref_39","unstructured":"(2021, October 03). ATGAM Info, Available online: https:\/\/dailymed.nlm.nih.gov\/dailymed\/drugInfo.cfm?setid=e19acee5-ff33-45a5-bbbf-801756bc59b4."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1177\/1060028015570729","article-title":"Ombitasvir\/Paritaprevir\/Ritonavir and Dasabuvir Tablets for Hepatitis C Virus Genotype 1 Infection","volume":"49","author":"Klibanov","year":"2015","journal-title":"Ann. Pharmacother."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1586\/17446651.2014.949672","article-title":"Defining the role of GLP-1 receptor agonists for individualized treatment of Type 2 diabetes","volume":"9","author":"Yabe","year":"2014","journal-title":"Expert Rev. Endocrinol. Metab."},{"key":"ref_42","unstructured":"Busard\u00f2, F.P., Kyriakou, C., Napoletano, S., Marinelli, E., and Zaami, S. (2021, November 04). Clinical Applications of Sodium Oxybate (GHB): From Narcolepsy to Alcohol Withdrawal Syndrome. Available online: https:\/\/www.europeanreview.org\/article\/9952."},{"key":"ref_43","first-page":"51","article-title":"JADER from Pharmacovigilance Point of View","volume":"19","author":"Maeda","year":"2014","journal-title":"Jpn. J. Pharmacoepidemiol. Ekigaku"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1002\/pds.3454","article-title":"Pilot evaluation of an automated method to decrease false-positive signals induced by co-prescriptions in spontaneous reporting databases","volume":"23","author":"Avillach","year":"2014","journal-title":"Pharmacoepidemiol. Drug Saf."},{"key":"ref_45","unstructured":"(2021, November 04). MedDRA. Available online: https:\/\/www.meddra.org\/26."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Kurosaki, K., Wu, R., and Uesawa, Y. (2020). A Toxicity Prediction Tool for Potential Agonist\/Antagonist Activities in Molecular Initiating Events Based on Chemical Structures. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21217853"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/1\/27\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:53:14Z","timestamp":1760169194000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/1\/27"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,24]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["ph15010027"],"URL":"https:\/\/doi.org\/10.3390\/ph15010027","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,24]]}}}