{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T18:57:56Z","timestamp":1780081076461,"version":"3.54.0"},"reference-count":84,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T00:00:00Z","timestamp":1750982400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Qatar University"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Tramadol is an opioid frequently prescribed for moderate to severe pain and has seen a global increase in use. This presents numerous challenges in clinical management. This study aims to elucidate metabolic signatures associated with tramadol consumption, enhancing predictive capabilities for therapeutic outcomes and optimizing patient-specific treatment plans. Methods: Data were obtained from the Qatar Biobank (QBB), focusing on pharmacogenomic variants associated with tramadol use and prescription trends. A cohort of 27 individuals who were administered daily tramadol doses between 100 and 400 mg with available metabolomic profiles were selected. The pharmacokinetics of tramadol were evaluated in relation to specific CYP2D6 genetic variants. Comparative pharmacometabolomic profiles were generated for tramadol users versus a control group of 54 non-users. Additionally, prescription data encompassing tramadol formulations were collected from the electronic medical records (EMR) system of the major public hospital network in Qatar (Hamad Medical Corporation) to discern prescribing patterns. Results: From January 2019 to December 2022, tramadol prescriptions varied, with chronic pain as the primary indication, followed by acute pain. Pharmacogenomic analysis indicated that CYP2D6 allele variations significantly impacted tramadol and O-desmethyltramadol glucuronide levels, notably in \u2018normal metabolizers\u2019. Metabolomic analysis revealed distinct metabolic profiles in tramadol users, with significant variations in phosphatidylcholine, histidine, and lysine pathways compared to controls, highlighting tramadol\u2019s unique biochemical impacts. Conclusions: This study underscores the importance of integrating genetic and omics-based approaches to enhance tramadol\u2019s efficacy and safety. These findings support personalized pain management strategies, enhancing treatment outcomes for both chronic and acute pain.<\/jats:p>","DOI":"10.3390\/ph18070971","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T07:55:43Z","timestamp":1751442943000},"page":"971","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Pharmacogenomics and Pharmacometabolomics in Precision Tramadol Prescribing for Enhanced Pain Management: Evidence from QBB and EMR Data"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4596-9942","authenticated-orcid":false,"given":"Dhoha","family":"Dhieb","sequence":"first","affiliation":[{"name":"Pharmaceutical Sciences Department, College of Pharmacy, QU Health, Qatar University, Doha P.O. Box 2713, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7263-4905","authenticated-orcid":false,"given":"Najeha","family":"Anwardeen","sequence":"additional","affiliation":[{"name":"Biomedical Research Center, QU Health, Qatar University, Doha P.O. Box 2713, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9425-7266","authenticated-orcid":false,"given":"Dinesh","family":"Velayutham","sequence":"additional","affiliation":[{"name":"College of Health & Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3803-4604","authenticated-orcid":false,"given":"Mohamed A.","family":"Elrayess","sequence":"additional","affiliation":[{"name":"Biomedical Research Center, QU Health, Qatar University, Doha P.O. Box 2713, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7747-0930","authenticated-orcid":false,"given":"Puthen Veettil","family":"Jithesh","sequence":"additional","affiliation":[{"name":"College of Health & Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2646-1123","authenticated-orcid":false,"given":"Kholoud","family":"Bastaki","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences Department, College of Pharmacy, QU Health, Qatar University, Doha P.O. Box 2713, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e46","DOI":"10.1097\/SLA.0000000000002623","article-title":"From Data to Practice","volume":"267","author":"Thiels","year":"2018","journal-title":"Ann. Surg."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1056\/NEJMp1714529","article-title":"The Public and the Opioid-Abuse Epidemic","volume":"378","author":"Blendon","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_3","unstructured":"(2025, February 16). Council of Economic Advisers Report: The Underestimated Cost of the Opioid Crisis. 20 November 2017, Available online: https:\/\/trumpwhitehouse.archives.gov\/briefings-statements\/cea-report-underestimated-cost-opioid-crisis\/."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/j.jpain.2012.03.009","article-title":"The economic costs of pain in the United States","volume":"13","author":"Gaskin","year":"2012","journal-title":"J. Pain"},{"key":"ref_5","unstructured":"Dydyk, A.M., and Conermann, T. (2024). Chronic Pain. StatPearls [Internet], StatPearls Publishing."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1177\/15291006211008157","article-title":"Psychological Interventions for the Treatment of Chronic Pain in Adults","volume":"22","author":"Driscoll","year":"2021","journal-title":"Psychol. Sci. Public Interest"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1186\/ar2147","article-title":"Arthritis and Pain. Current Approaches in the Treatment of Arthritic Pain","volume":"9","author":"Kidd","year":"2007","journal-title":"Arthritis Res. Ther."},{"key":"ref_8","unstructured":"Tauben, D., and Stacey, B.R. (2020). Pharmacologic Management of Chronic Non-Cancer Pain in Adults, UpToDate."},{"key":"ref_9","unstructured":"(2025, February 16). US FDA Label Information for Tramadol, Available online: https:\/\/www.fda.gov\/drugs\/postmarket-drug-safety-information-patients-and-providers\/tramadol-information."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e119156","DOI":"10.5812\/aapm.119156","article-title":"Full Opioid Agonists and Tramadol: Pharmacological and Clinical Considerations","volume":"11","author":"Edinoff","year":"2021","journal-title":"Anesthesiol. Pain Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.biopha.2018.12.085","article-title":"An Overview of Tramadol and Its Usage in Pain Management and Future Perspective","volume":"111","author":"Subedi","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6838","DOI":"10.3390\/curroncol30070500","article-title":"Cancer Pain Management: A Narrative Review of Current Concepts, Strategies, and Techniques","volume":"30","author":"Mestdagh","year":"2023","journal-title":"Curr. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"18","DOI":"10.2165\/00003495-199700532-00006","article-title":"Pharmacologie Du Tramadol","volume":"53","author":"Dayer","year":"1997","journal-title":"Drugs"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"879","DOI":"10.2165\/00003088-200443130-00004","article-title":"Clinical Pharmacology of Tramadol","volume":"43","author":"Grond","year":"2004","journal-title":"Clin. Pharmacokinet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1097\/FPC.0000000000000057","article-title":"PharmGKB Summary","volume":"24","author":"Gong","year":"2014","journal-title":"Pharmacogenet. Genom."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1213\/ANE.0000000000001683","article-title":"Trends in Tramadol: Pharmacology, Metabolism, and Misuse","volume":"124","author":"Miotto","year":"2017","journal-title":"Anesth. Analg."},{"key":"ref_17","unstructured":"(2025, February 16). Harrigan TM Schedules of Controlled Substances: Placement of Tramadol into Schedule IV, Available online: https:\/\/www.federalregister.gov\/documents\/2014\/07\/02\/2014-15548\/schedules-of-controlled-substances-placement-of-tramadol-into-schedule-iv."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Dunn, K.E., Bergeria, C.L., Huhn, A.S., and Strain, E.C. (2019). A Systematic Review of Laboratory Evidence for the Abuse Potential of Tramadol in Humans. Front. Psychiatry, 10.","DOI":"10.3389\/fpsyt.2019.00704"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1002\/ejp.1196","article-title":"Comparative Pharmacology and Toxicology of Tramadol and Tapentadol","volume":"22","author":"Faria","year":"2018","journal-title":"Eur. J. Pain"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1055\/a-0646-3918","article-title":"Demographic Characteristics and Functional Performance of the Kidneys and Hearts of Patients with Acute Tramadol Toxicity","volume":"69","author":"Mohammadpour","year":"2019","journal-title":"Drug Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1097\/PEC.0000000000001084","article-title":"Characterizing the Toxicity and Dose-Effect Profile of Tramadol Ingestions in Children","volume":"35","author":"Stassinos","year":"2019","journal-title":"Pediatr. Emerg. Care"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1007\/s00228-014-1799-2","article-title":"Effects of Terbinafine and Itraconazole on the Pharmacokinetics of Orally Administered Tramadol","volume":"71","author":"Saarikoski","year":"2015","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1007\/BF00180294","article-title":"The Metabolism of Tramadol by Human Liver Microsomes","volume":"70","author":"Paar","year":"1992","journal-title":"Clin. Investig."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/s002280050368","article-title":"Polymorphic CYP2D6 Mediates O-Demethylation of the Opioid Analgesic Tramadol","volume":"53","author":"Paar","year":"1997","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_25","first-page":"1146","article-title":"Identification of Cytochrome P-450 Isoforms Responsible for Cis-Tramadol Metabolism in Human Liver Microsomes","volume":"29","author":"Subrahmanyam","year":"2001","journal-title":"Drug Metab. Dispos."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1358\/dot.2008.44.11.1289441","article-title":"Tramadol: Basic Pharmacology and Emerging Concepts","volume":"44","author":"Reeves","year":"2008","journal-title":"Drugs Today"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"663","DOI":"10.2217\/pgs-2020-0026","article-title":"Involvement of CYP2D6 and CYP2B6 on Tramadol Pharmacokinetics","volume":"21","author":"Ochoa","year":"2020","journal-title":"Pharmacogenomics"},{"key":"ref_28","unstructured":"The Pharmacogene Variation (PharmVar) Consortium (2025, February 16). CYP2D6 Allele Nomenclature. Available online: https:\/\/www.pharmvar.org\/gene\/CYP2D6."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/sj.clpt.6100406","article-title":"The CYP2D6 Activity Score: Translating Genotype Information into a Qualitative Measure of Phenotype","volume":"83","author":"Gaedigk","year":"2008","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/gim.2016.87","article-title":"Standardizing Terms for Clinical Pharmacogenetic Test Results: Consensus Terms from the Clinical Pharmacogenetics Implementation Consortium (CPIC)","volume":"19","author":"Caudle","year":"2017","journal-title":"Genet. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.forsciint.2010.07.011","article-title":"Pharmacogenetics and Forensic Toxicology","volume":"203","author":"Musshoff","year":"2010","journal-title":"Forensic Sci. Int."},{"key":"ref_32","unstructured":"41st ECDD Meeting Geneva: WHO Expert Committee on Drug Dependence (2025, March 09). Critical Review Report: Tramadol. Geneva, 12\u201316 November 2018. Available online: https:\/\/ecddrepository.org\/sites\/default\/files\/2023-04\/tramadol.pdf."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"582","DOI":"10.3109\/10826084.2014.991406","article-title":"Medical and Psychiatric Effects of Long-Term Dependence on High Dose of Tramadol","volume":"50","author":"Helaly","year":"2015","journal-title":"Subst. Use Misuse"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1192\/bji.2021.53","article-title":"Tramadol, Captagon and Khat Use in the Eastern Mediterranean Region: Opening Pandora\u2019s Box","volume":"19","author":"Akbari","year":"2022","journal-title":"BJPsych Int."},{"key":"ref_35","unstructured":"United Nations Office on Drugs and Crime (UNODC) (2025, March 09). Regional Overview Asia and Oceania. Available online: https:\/\/www.unodc.org\/documents\/scientific\/Regional_Overview_Asia_and_Oceania.pdf."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Zhang, R., Lin, Y., Wu, Y., Deng, L., Zhang, H., Liao, M., and Peng, Y. (2024). MvMRL: A Multi-View Molecular Representation Learning Method for Molecular Property Prediction. Brief Bioinform., 25.","DOI":"10.1093\/bib\/bbae298"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Yang, Z., Liu, X., Xu, H., Teschendorff, A.E., Xu, L., Li, J., Fu, M., Liu, J., Zhou, H., and Wang, Y. (2024). Integrative Analysis of Genomic and Epigenomic Regulation Reveals MiRNA Mediated Tumor Heterogeneity and Immune Evasion in Lower Grade Glioma. Commun. Biol., 7.","DOI":"10.1038\/s42003-024-06488-9"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1842","DOI":"10.1038\/s41436-018-0431-8","article-title":"CYP2D6-Guided Opioid Therapy Improves Pain Control in CYP2D6 Intermediate and Poor Metabolizers: A Pragmatic Clinical Trial","volume":"21","author":"Smith","year":"2019","journal-title":"Genet. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"397","DOI":"10.2217\/pgs-2018-0205","article-title":"Drug\u2013Gene and Drug\u2013Drug Interactions Associated with Tramadol and Codeine Therapy in the INGENIOUS Trial","volume":"20","author":"Fulton","year":"2019","journal-title":"Pharmacogenomics"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.jcin.2017.07.022","article-title":"Multisite Investigation of Outcomes With Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention","volume":"11","author":"Cavallari","year":"2018","journal-title":"JACC Cardiovasc. Interv."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1038\/clpt.2013.254","article-title":"Clinical Pharmacogenetics Implementation Consortium Guidelines for Cytochrome P450 2D6 Genotype and Codeine Therapy: 2014 Update","volume":"95","author":"Crews","year":"2014","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.neuroscience.2016.04.041","article-title":"Genetic Predictors of Human Chronic Pain Conditions","volume":"338","author":"Meloto","year":"2016","journal-title":"Neuroscience"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1159\/000527041","article-title":"Chronic Pain and Psychiatric Conditions","volume":"9","author":"Johnston","year":"2023","journal-title":"Complex. Psychiatry"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1097\/ADM.0000000000000380","article-title":"Opioid Use Disorders Attributed to Tramadol Among Egyptian University Students","volume":"12","author":"Bassiony","year":"2018","journal-title":"J. Addict. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"26","DOI":"10.17795\/ajnpp-20314","article-title":"Prevalence and Factors Associated with Tramadol Abuse Among College Students in West of Iran: An Application of the Theory of Planned Behavior","volume":"1","author":"Bashirian","year":"2014","journal-title":"Avicenna J. Neuro Psycho Physiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1080\/02791072.2019.1612125","article-title":"Explosive Increase in Tramadol Use in Korea 2003\u20132013: Analysis of Patient Trends Based on the Korea National Health Insurance Database","volume":"52","author":"Kim","year":"2020","journal-title":"J. Psychoact. Drugs"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1080\/02791072.2019.1671638","article-title":"Substance Dependence and Hepatitis among Tramadol Prescription Users: A Study of Former Adolescent Psychiatric Inpatients in Northern Finland","volume":"52","author":"Hakko","year":"2020","journal-title":"J. Psychoact. Drugs"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Zhang, H., and Liu, Z. (2013). The Investigation of Tramadol Dependence with No History of Substance Abuse: A Cross-Sectional Survey of Spontaneously Reported Cases in Guangzhou City, China. Biomed. Res. Int., 2013.","DOI":"10.1155\/2013\/283425"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1037\/a0022721","article-title":"Examining the Use of Tramadol Hydrochloride as an Antidepressant","volume":"19","author":"Barber","year":"2011","journal-title":"Exp. Clin. Psychopharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Martyn-St James, M., Cooper, K., Kaltenthaler, E., Dickinson, K., Cantrell, A., Wylie, K., Frodsham, L., and Hood, C. (2015). Tramadol for Premature Ejaculation: A Systematic Review and Meta-Analysis. BMC Urol., 15.","DOI":"10.1186\/1471-2490-15-6"},{"key":"ref_51","first-page":"9574395","article-title":"Tramadol-Induced Mood Elevation in a Patient with No Previous Psychiatric History","volume":"2018","author":"Osman","year":"2018","journal-title":"Case Rep. Psychiatry"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"758","DOI":"10.2174\/1871527318666191112124435","article-title":"Neurobehavioral Consequences Associated with Long Term Tramadol Utilization and Pathological Mechanisms","volume":"18","author":"Raj","year":"2020","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1080\/09687637.2023.2263144","article-title":"Drug Use Trajectories among Young People with Experiences of Problematic Tramadol Use","volume":"31","author":"Arve","year":"2023","journal-title":"Drugs Educ. Prev. Policy"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1213\/ANE.0b013e31825683c3","article-title":"Antihypersensitivity Effects of Tramadol Hydrochloride in a Rat Model of Postoperative Pain","volume":"115","author":"Kimura","year":"2012","journal-title":"Anesth. Analg."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.biopha.2018.11.141","article-title":"Chronic Exposure to the Opioid Tramadol Induces Oxidative Damage, Inflammation and Apoptosis, and Alters Cerebral Monoamine Neurotransmitters in Rats","volume":"110","author":"Mohamed","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"545","DOI":"10.3109\/15563650.2015.1036279","article-title":"Tramadol Overdose Causes Seizures and Respiratory Depression but Serotonin Toxicity Appears Unlikely","volume":"53","author":"Ryan","year":"2015","journal-title":"Clin. Toxicol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"685","DOI":"10.4103\/0259-1162.191110","article-title":"Tramadol Side Effects: Seizure and Hypoglycemia","volume":"10","author":"Shubhakaran","year":"2016","journal-title":"Anesth. Essays Res."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Makunts, T., U, A., Atayee, R.S., and Abagyan, R. (2019). Retrospective Analysis Reveals Significant Association of Hypoglycemia with Tramadol and Methadone in Contrast to Other Opioids. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-48955-y"},{"key":"ref_59","first-page":"540","article-title":"Neuronal Apoptosis in Morphine Addiction and Its Molecular Mechanism","volume":"6","author":"Liu","year":"2013","journal-title":"Int. J. Clin. Exp. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1177\/0748233713491814","article-title":"Effects of Tramadol, Clonazepam, and Their Combination on Brain Mitochondrial Complexes","volume":"31","author":"Mohamed","year":"2015","journal-title":"Toxicol. Ind. Health"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3351","DOI":"10.1016\/j.jprot.2012.03.038","article-title":"Effects of Chronic Tramadol Exposure on the Zebrafish Brain: A Proteomic Study","volume":"75","author":"Zhuo","year":"2012","journal-title":"J. Proteom."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Xia, W., Liu, G., Shao, Z., Xu, E., Yuan, H., Liu, J., and Gao, L. (2020). Toxicology of Tramadol Following Chronic Exposure Based on Metabolomics of the Cerebrum in Mice. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-67974-8"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Jiang, S., Liu, G., Yuan, H., Xu, E., Xia, W., Zhang, X., Liu, J., and Gao, L. (2021). Changes on Proteomic and Metabolomic Profile in Serum of Mice Induced by Chronic Exposure to Tramadol. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-81109-7"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Muhn, S., Amin, N.S., Bardolia, C., Del Toro-Pag\u00e1n, N., Pizzolato, K., Thacker, D., Turgeon, J., Tomaino, C., and Michaud, V. (2022). Pharmacogenomics and Drug-Induced Phenoconversion Informed Medication Safety Review in the Management of Pain Control and Quality of Life: A Case Report. J. Pers. Med., 12.","DOI":"10.3390\/jpm12060974"},{"key":"ref_65","unstructured":"Dean, L., and Kane, M. (2012). Tramadol Therapy and CYP2D6 Genotype. Medical Genetics Summaries [Internet], National Center for Biotechnology Information (US)."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Mostafa, S., Polasek, T.M., Sheffield, L.J., Huppert, D., and Kirkpatrick, C.M.J. (2021). Quantifying the Impact of Phenoconversion on Medications With Actionable Pharmacogenomic Guideline Recommendations in an Acute Aged Persons Mental Health Setting. Front. Psychiatry, 12.","DOI":"10.3389\/fpsyt.2021.724170"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Klomp, S.D., Manson, M.L., Guchelaar, H.-J., and Swen, J.J. (2020). Phenoconversion of Cytochrome P450 Metabolism: A Systematic Review. J. Clin. Med., 9.","DOI":"10.3390\/jcm9092890"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1111\/bcp.12441","article-title":"Addressing Phenoconversion: The Achilles\u2019 Heel of Personalized Medicine","volume":"79","author":"Shah","year":"2015","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1002\/cpt.2354","article-title":"How to Integrate CYP2D6 Phenoconversion into Clinical Pharmacogenetics: A Tutorial","volume":"110","author":"Cicali","year":"2021","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Sheweita, S.A., Almasmari, A.A., and El-Banna, S.G. (2018). Tramadol-Induced Hepato- and Nephrotoxicity in Rats: Role of Curcumin and Gallic Acid as Antioxidants. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0202110"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Liu, B., Chen, A., Lan, J., Ren, L., Wei, Y., and Gao, L. (2019). Protective Mechanism of 1-Methylhydantoin against Lung Injury Induced by Paraquat Poisoning. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0222521"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/S0022-3565(25)11227-5","article-title":"Opioid and Nonopioid Components Independently Contribute to the Mechanism of Action of Tramadol, an \u201catypical\u201d Opioid Analgesic","volume":"260","author":"Raffa","year":"1992","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1152\/physrev.00043.2007","article-title":"Histamine in the Nervous System","volume":"88","author":"Haas","year":"2008","journal-title":"Physiol. Rev."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Zeisel, S. (2017). Choline, Other Methyl-Donors and Epigenetics. Nutrients, 9.","DOI":"10.3390\/nu9050445"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.neuropharm.2013.04.004","article-title":"Epigenetic Mechanisms of Drug Addiction","volume":"76","author":"Nestler","year":"2014","journal-title":"Neuropharmacology"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.brainresrev.2008.03.002","article-title":"Cellular and Molecular Mechanisms Involved in the Neurotoxicity of Opioid and Psychostimulant Drugs","volume":"58","author":"Rego","year":"2008","journal-title":"Brain Res. Rev."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"11692","DOI":"10.1073\/pnas.1102715108","article-title":"GABA Exerts Protective and Regenerative Effects on Islet Beta Cells and Reverses Diabetes","volume":"108","author":"Soltani","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.brainres.2018.03.015","article-title":"Neurotransmitter Modulation by the Gut Microbiota","volume":"1693","author":"Strandwitz","year":"2018","journal-title":"Brain Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1002\/da.20262","article-title":"Role of GABA in Anxiety and Depression","volume":"24","author":"Kalueff","year":"2007","journal-title":"Depress. Anxiety"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1038\/nrd870","article-title":"Endogenous Kynurenines as Targets for Drug Discovery and Development","volume":"1","author":"Stone","year":"2002","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1093\/aje\/kwz084","article-title":"Qatar Biobank Cohort Study: Study Design and First Results","volume":"188","author":"Fthenou","year":"2019","journal-title":"Am. J. Epidemiol."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Suhre, K., Stephan, N., Zaghlool, S., Triggle, C.R., Robinson, R.J., Evans, A.M., and Halama, A. (2022). Matching Drug Metabolites from Non-Targeted Metabolomics to Self-Reported Medication in the Qatar Biobank Study. Metabolites, 12.","DOI":"10.3390\/metabo12030249"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41525-022-00281-5","article-title":"A Population Study of Clinically Actionable Genetic Variation Affecting Drug Response from the Middle East","volume":"7","author":"Jithesh","year":"2022","journal-title":"NPJ Genom. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1038\/s41467-021-21381-3","article-title":"Whole Genome Sequencing in the Middle Eastern Qatari Population Identifies Genetic Associations with 45 Clinically Relevant Traits","volume":"12","author":"Thareja","year":"2021","journal-title":"Nat. Commun."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/7\/971\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:00:18Z","timestamp":1760032818000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/7\/971"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,27]]},"references-count":84,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["ph18070971"],"URL":"https:\/\/doi.org\/10.3390\/ph18070971","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,27]]}}}