{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:50:56Z","timestamp":1787028656392,"version":"build-2736575974"},"reference-count":46,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,2,20]],"date-time":"2025-02-20T00:00:00Z","timestamp":1740009600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background\/Objectives: There exist multiple opioid-based treatments in palliative care, each with distinct side effect profiles. When adverse events occur, switching opioids can help maintain effective pain management. However, owing to limited clinical evidence, no comprehensive guidelines exist for opioid switching. This study employed the Side Effect Resource (SIDER) database, which aggregates adverse event data from clinical trials and package inserts, to analyze the side effects of five commonly used \u201cstrong opioids\u201d in palliative care in Japan, namely morphine, fentanyl, oxycodone, hydromorphone, and tapentadol. Methods: Data on the names and incidence of adverse events for each opioid were extracted from SIDER 4.1, developed by the Max Delbr\u00fcck Center for Molecular Medicine. Cluster analysis and principal component analysis were performed to interpret the data. Results: The key side effects of opioids were nausea, vomiting, constipation, and drowsiness. Fentanyl was more frequently associated with nausea and vomiting but less frequently with constipation and drowsiness. Tapentadol caused nausea relatively more frequently and constipation less frequently. Oxycodone was prominently linked to drowsiness, whereas morphine was frequently associated with constipation and drowsiness. Hydromorphone was associated with higher rates of constipation and vomiting but lower incidences of nausea and drowsiness. Conclusions: All side effects characterizing the opioids were related to \u03bc-opioid receptor stimulation, although the present study findings highlight differences in the frequency of specific side effects among the opioids. These results provide objective insights that can guide opioid switching in response to adverse effects.<\/jats:p>","DOI":"10.3390\/jcm14051410","type":"journal-article","created":{"date-parts":[[2025,2,20]],"date-time":"2025-02-20T04:53:39Z","timestamp":1740027219000},"page":"1410","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Comprehensive Analysis of Strong Opioid Side Effects in Palliative Care Using the SIDER Database"],"prefix":"10.3390","volume":"14","author":[{"given":"Risako","family":"Hirai","sequence":"first","affiliation":[{"name":"Department of Medical Molecular Informatics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motoki","family":"Kei","sequence":"additional","affiliation":[{"name":"Department of Medical Molecular Informatics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan"},{"name":"Department of Pharmacy, Tokyo Women\u2019s Medical University Adachi Medical Center, 4-33-1 Kohoku, Adachi-ku, Tokyo 123-8558, 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":[[2025,2,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1126\/science.1239403","article-title":"Constitutive \u03bc-opioid receptor activity leads to long-term endogenous analgesia and dependence","volume":"341","author":"Corder","year":"2013","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3903","DOI":"10.1200\/JCO.2007.15.9533","article-title":"Evidence-based recommendations for cancer nausea and vomiting","volume":"26","author":"Naeim","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"ref_3","unstructured":"(2025, February 18). Japan Society of Clinical Oncology. Available online: http:\/\/www.jsco-cpg.jp\/."},{"key":"ref_4","first-page":"CD012592","article-title":"Opioids for cancer pain\u2014An overview of Cochrane reviews","volume":"7","author":"Wiffen","year":"2017","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_5","first-page":"CD012509","article-title":"Adverse events associated with medium- and long-term use of opioids for chronic non-cancer pain: An overview of cochrane reviews","volume":"10","author":"Els","year":"2017","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"S105","DOI":"10.36076\/ppj.2008\/11\/S105","article-title":"Opioid complications and side effects","volume":"11","author":"Benyamin","year":"2008","journal-title":"Pain Physician"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1177\/082585979300900204","article-title":"Results of antiemetic management in terminal illness","volume":"9","author":"Lichter","year":"1993","journal-title":"J. Palliat. Care"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1016\/S0885-3924(02)00391-3","article-title":"A pilot exploration of the antiemetic activity of olanzapine for the relief of nausea in patients with advanced cancer and pain","volume":"23","author":"Passik","year":"2002","journal-title":"J. Pain Symptom Manag."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0885-3924(97)00276-5","article-title":"Efficacy of senna versus lactulose in terminal cancer patients treated with opioids","volume":"15","author":"Agra","year":"1998","journal-title":"J. Pain Symptom Manag."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1002\/ijc.11416","article-title":"Long-term cancer pain management in morphine pre-treated and opioid naive patients with transdermal fentanyl","volume":"107","author":"Mystakidou","year":"2003","journal-title":"Int. J. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1176\/ajp.153.2.231","article-title":"A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients","volume":"153","author":"Breitbart","year":"1996","journal-title":"Am. J. Psychiat."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Candy, B., Jackson, K.C., Jones, L., Leurent, B., Tookman, A., and King, M. (2012). Drug therapy for delirium in terminally ill adult patients. Cochrane Database Syst. Rev., 11.","DOI":"10.1002\/14651858.CD004770.pub2"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3049","DOI":"10.1002\/cncr.10518","article-title":"A prospective study evaluating the response of patients with unrelieved cancer pain to parenteral opioids","volume":"94","author":"Enting","year":"2002","journal-title":"Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1089\/jpm.2021.0438","article-title":"Revision of pharmacological treatment recommendations for cancer pain: Clinical guidelines from the Japanese Society of Palliative Medicine","volume":"25","author":"Mawatari","year":"2022","journal-title":"J. Palliat. Med."},{"key":"ref_15","unstructured":"(2025, February 18). SIDER Side Effect Resource. Available online: http:\/\/sideeffects.embl.de\/."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"D1075","DOI":"10.1093\/nar\/gkv1075","article-title":"The SIDER database of drugs and side effects","volume":"44","author":"Kuhn","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Kuhn, M., Campillos, M., Letunic, I., Jensen, L.J., and Bork, P. (2010). A side effect resource to capture phenotypic effects of drugs. Mol. Syst. Biol., 6.","DOI":"10.1038\/msb.2009.98"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Iqbal, E., Govind, R., Romero, A., Dzahini, O., Broadbent, M., Stewart, R., Smith, T., Kim, C.-H., Werbeloff, N., and MacCabe, J.H. (2020). The side effect profile of clozapine in real world data of three large mental health hospitals. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0243437"},{"key":"ref_19","unstructured":"(2025, February 18). Guidelines for the Pharmacological Treatment of Cancer Pain. Available online: https:\/\/www.jspm.ne.jp\/publication\/guidelines\/individual.html?entry_id=85."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1007\/s00357-014-9161-z","article-title":"Ward\u2019s hierarchical agglomerative clustering method: Which algorithms implement ward\u2019s criterion?","volume":"31","author":"Murtagh","year":"2014","journal-title":"J. Classif."},{"key":"ref_21","first-page":"20150202","article-title":"Principal component analysis: A review and recent developments","volume":"374","author":"Jolliffe","year":"2016","journal-title":"Philos. Trans. A Math. Phys. Eng. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.critrevonc.2015.12.011","article-title":"Opioid switching in cancer pain: From the beginning to nowadays","volume":"99","author":"Mercadante","year":"2016","journal-title":"Crit. Rev. Oncol. Hemat."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1185\/03007990902816970","article-title":"Tolerability of tapentadol immediate release in patients with lower back pain or osteoarthritis of the hip or knee over 90 days: A randomized, double-blind study","volume":"25","author":"Hale","year":"2009","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1007\/s12325-011-0018-0","article-title":"Comparable efficacy and superior gastrointestinal tolerability (nausea, vomiting, constipation) of tapentadol compared with oxycodone hydrochloride","volume":"28","author":"Etropolski","year":"2011","journal-title":"Adv. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1007\/s40261-014-0204-3","article-title":"Ready conversion of patients with well-controlled, moderate to severe, chronic malignant tumor\u2013related pain on other opioids to tapentadol extended release","volume":"34","author":"Imanaka","year":"2014","journal-title":"Clin. Drug Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1213\/ANE.0000000000003368","article-title":"Lack of evidence for ceiling effect for buprenorphine analgesia in humans","volume":"127","author":"Richardson","year":"2018","journal-title":"Anesth. Analg."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Zhong, W., Shahbaz, O., Teskey, G., Beever, A., Kachour, N., Venketaraman, V., and Darmani, N.A. (2021). Mechanisms of nausea and vomiting: Current knowledge and recent advances in intracellular emetic signaling systems. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115797"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1111\/j.1526-4637.2009.00583.x","article-title":"Nausea and vomiting side effects with opioid analgesics during treatment of chronic pain: Mechanisms, implications, and management options","volume":"10","author":"Porreca","year":"2009","journal-title":"Pain Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"51","DOI":"10.4097\/kjae.2016.69.1.51","article-title":"Effects of intraoperative single bolus fentanyl administration and remifentanil infusion on postoperative nausea and vomiting","volume":"69","author":"Lim","year":"2016","journal-title":"Korean J. Anesthesiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1111\/j.1365-2044.1992.tb02323.x","article-title":"Ventilatory effects of subarachnoid fentanyl in the elderly","volume":"47","author":"Varrassi","year":"1992","journal-title":"Anaesthesia"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/s40261-014-0249-3","article-title":"A pooled analysis evaluating the efficacy and tolerability of tapentadol extended release for chronic, painful diabetic peripheral neuropathy","volume":"35","author":"Schwartz","year":"2015","journal-title":"Clin. Drug Investig."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.3748\/wjg.v18.i12.1391","article-title":"Opiate-induced constipation related to activation of small intestine opioid \u03bc2-receptors","volume":"18","author":"Chen","year":"2012","journal-title":"World J. Gastroenterol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"41","DOI":"10.15403\/jgld.2014.1121.281.any","article-title":"Efficacy of naldemedine for the treatment of opioid-induced constipation: A meta-analysis","volume":"28","author":"Esmadi","year":"2019","journal-title":"J. Gastrointestin. Liver Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1111\/nmo.12443","article-title":"Site and mechanism of morphine tolerance in the gastrointestinal tract","volume":"26","author":"Akbarali","year":"2014","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1093\/toxsci\/kfv055","article-title":"Morphine-induced constipation develops with increased aquaporin-3 expression in the colon via increased serotonin secretion","volume":"145","author":"Kon","year":"2015","journal-title":"Toxicol. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1124\/jpet.108.143438","article-title":"Morphine tolerance in the mouse ileum and colon","volume":"327","author":"Ross","year":"2008","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Zhang, L., Zhang, J.-T., Hang, L., and Liu, T. (2020). Mu opioid receptor heterodimers emerge as novel therapeutic targets: Recent progress and future perspective. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.01078"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e6286","DOI":"10.1097\/MD.0000000000006286","article-title":"Oxycodone versus fentanyl for intravenous patient-controlled analgesia after laparoscopic supracervical hysterectomy: A prospective, randomized, double-blind study","volume":"96","author":"Kim","year":"2017","journal-title":"Medicine"},{"key":"ref_39","first-page":"CD002763","article-title":"Single dose oral oxycodone and oxycodone plus paracetamol (acetaminophen) for acute postoperative pain in adults","volume":"8","author":"Gaskell","year":"2009","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1093\/bja\/50.6.605","article-title":"A double-blind comparison of morphine and buprenorphine in the prevention of pain after operation","volume":"50","author":"Kay","year":"1978","journal-title":"Br. J. Anaesth."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Bao, Y.J., Hou, W., Kong, X.Y., Yang, L., Xia, J., Hua, B.J., and Knaggs, R. (2016). Hydromorphone for cancer pain. Cochrane Database Syst. Rev., 10.","DOI":"10.1002\/14651858.CD011108.pub2"},{"key":"ref_42","first-page":"5697","article-title":"Effects of hydromorphone and morphine intravenous analgesia on plasma motilin and postoperative nausea and vomiting in patients undergoing total hysterectomy","volume":"22","author":"Liu","year":"2018","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Im, J.J., Na, S., Kang, S., Jeong, H., Lee, E.-S., Lee, T.-K., Ahn, W.-Y., Chung, Y.-A., and Song, I.-U. (2022). A randomized, double-blind, sham-controlled trial of transcranial direct current stimulation for the treatment of persistent postural-perceptual dizziness (PPPD). Front. Neurol., 13.","DOI":"10.3389\/fneur.2022.868976"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1016\/j.jpainsymman.2011.12.280","article-title":"Safety and tolerability of once-daily OROS\u00ae hydromorphone extended-release in opioid-tolerant adults with moderate-to-severe chronic cancer and noncancer pain: Pooled analysis of 11 clinical studies","volume":"44","author":"Nalamachu","year":"2012","journal-title":"J. Pain Symptom Manag."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1177\/1049909106289068","article-title":"The adverse effects of morphine: A prospective survey of common symptoms during repeated dosing for chronic cancer pain","volume":"23","author":"Glare","year":"2006","journal-title":"Am. J. Hosp. Palliat. Care"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"S21","DOI":"10.1016\/j.jaad.2006.02.032","article-title":"Acute generalized exanthematous pustulosis caused by morphine, confirmed by positive patch test and lymphocyte transformation test","volume":"55","author":"Kardaun","year":"2006","journal-title":"J. Am. Acad. Dermatol."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/5\/1410\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:38:36Z","timestamp":1760027916000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/5\/1410"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,20]]},"references-count":46,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["jcm14051410"],"URL":"https:\/\/doi.org\/10.3390\/jcm14051410","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,20]]}}}