{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T06:57:45Z","timestamp":1792047465107,"version":"4.4.0"},"reference-count":67,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T00:00:00Z","timestamp":1762732800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000865","name":"Gates Foundation","doi-asserted-by":"publisher","award":["INV-036801"],"award-info":[{"award-number":["INV-036801"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["gatesopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Gates Open Res"],"abstract":"<ns3:p>\n                    Background Sickle Cell Disease (SCD) is highly prevalent in Nigeria, with severe pain crises being a primary cause of morbidity. Codeine and tramadol are frequently used opioids, but their effectiveness and safety are significantly influenced by\n                    <ns3:italic>CYP2D6<\/ns3:italic>\n                    genetic variations. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines exist for opioid therapy based on CYP2D6 phenotypes. There\u2019s a critical need for pre-emptive pharmacogenomic (PGx) testing in African SCD patients to guide opioid selection. This study aimed to determine\n                    <ns3:italic>CYP2D6<\/ns3:italic>\n                    allele, phenotype frequencies and evaluate the feasibility of implementing pre-emptive pharmacogenomic (PGx) testing to guide opioid therapy for SCD patients in Nigeria. Methods This prospective, multicenter implementation study recruited 503 consenting SCD patients (HbSS or HbSC) aged \u226515 years from five Nigerian sites. Blood samples were collected for DNA extraction.\n                    <ns3:italic>CYP2D6<\/ns3:italic>\n                    single-nucleotide polymorphisms and copy number variations were determined using Taqman assays based open array, GenoPharm. Phenotypes were assigned based on Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines using the Genomics Information Management System (GIMS). and patient-specific medication safety cards were generated. Results We successfully genotyped 503 SCD patients with a mean age of 25.1 years, while 61.4% were female, and hydroxyurea use was less than 9.4%. Actionable\n                    <ns3:italic>CYP2D6<\/ns3:italic>\n                    variants were found in 36.6% of participants. The predicted phenotype distribution was 8.8% Ultrarapid Metabolizers (UM), 54.1% Normal Metabolizers (NM), 26.0% Intermediate Metabolizers (IM), and 1.8% Poor Metabolizers (PM), with 9.3% undetermined. Patient medication safety cards were provided to guide prescriptions. Conclusions This study successfully established a genotyped cohort of 503 Nigerian SCD patients, demonstrating the feasibility of pre-emptive pharmacogenetic testing through a Pan-African collaborative model in a resource-limited setting. The identification of PM and UM provides direct clinical guidance, as CPIC guidelines recommend avoiding codeine and tramadol in these groups due to the high risk of diminished efficacy or serious toxicity, respectively. The high prevalence of actionable CYP2D6 variants indicates a substantial proportion of Nigerian SCD patients may experience altered opioid responses, underscoring the need for tailored prescribing to optimise pain control and minimise adverse drug reactions.\n                  <\/ns3:p>","DOI":"10.12688\/gatesopenres.16370.1","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T11:45:08Z","timestamp":1762775108000},"page":"101","update-policy":"https:\/\/doi.org\/10.12688\/gatesopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["CYP2D6 Pharmacogenetics in Nigerian Sickle Cell Disease: Phase 1 of Implementing Pharmacogenomics Testing for Effective Care and Treatment in Africa\u00a0(iPROTECTA) program"],"prefix":"10.12688","volume":"9","author":[{"given":"Babatunde","family":"Adeagbo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olusola","family":"Olarewaju","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ochuko","family":"Orherhe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zedias","family":"Chikwambi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian","family":"Mazhindu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahman","family":"Bolarinwa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oluseye","family":"Bolaji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Collen","family":"Masimirembwa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Consortium for Genomics and Therapeutics in Africa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2560","published-online":{"date-parts":[[2025,11,10]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"199-205","DOI":"10.1080\/16078454.2021.1880752","article-title":"Management of sickle cell disease: current practices and challenges in a northeastern region of the Democratic Republic of the Congo.","volume":"26","author":"P Kambale-Kombi","year":"2021","journal-title":"Hematology."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"609-620","DOI":"10.1080\/17474086.2019.1631155","article-title":"Current perspectives of sickle cell disease in Nigeria: changing the narratives.","volume":"12","author":"O Ojewunmi","year":"2019","journal-title":"Expert Rev. Hematol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1377-1384","DOI":"10.1016\/J.SJBS.2019.03.003","article-title":"Biochemical and molecular analysis of the beta-globin gene on Saudi sickle cell anemia.","volume":"26","author":"F Alenzi","year":"2019","journal-title":"Saudi J. Biol. Sci."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"2392-2400","DOI":"10.1182\/BLOOD.2020007645","article-title":"Fetal hemoglobin in sickle cell anemia.","volume":"136","author":"M Steinberg","year":"2020","journal-title":"Blood."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"197-201","DOI":"10.4103\/njm.njm_17_22","article-title":"Preventive measures of vaso-occlusive crisis among sickle cell disease patients in South-Eastern Nigeria.","volume":"31","author":"C Efobi","year":"2022","journal-title":"Niger. J. Med."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"5453-5455","DOI":"10.1182\/blood-2022-167948","article-title":"Insights into Vaso-Occlusive Crises-Related Readmissions in Patients with SCD across Geographic Regions.","volume":"140","author":"R Colombatti","year":"2022","journal-title":"Blood."},{"key":"ref7","article-title":"Clinical features of sickle cell anaemia in Northern Nigerian children.","volume":"31","author":"Y Mava","year":"2012","journal-title":"West Africa J. Med."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"17-27","DOI":"10.9734\/ajpr\/2023\/v12i1230","article-title":"Prevalence, pattern of disease and outcome of children with sickle cell disease admitted in a private health facility in Southern Nigeria.","volume":"12","author":"B West","year":"2023","journal-title":"Asian J. Pediatr. Res."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"3-14","DOI":"10.1179\/136485907X154638","article-title":"Sickle cell disease in Africa: Burden and research priorities.","volume":"101","author":"J Makani","year":"2007","journal-title":"Ann. Trop. Med. Parasitol."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"3503-3515","DOI":"10.2147\/ijgm.s410015","article-title":"Impact of sickle cell disease on affected individuals in Nigeria: A critical review.","volume":"16","author":"O Adigwe","year":"2023","journal-title":"Int. J. Gen. Med."},{"key":"ref11","doi-asserted-by":"publisher","DOI":"10.20944\/preprints202505.2130.v1","article-title":"Global sickle cell Disease and impact on school education in children; A focus on interventions for improving academic performance.","author":"R Birudu","year":"May 27, 2025"},{"key":"ref12","article-title":"A comparative study of academic achievement of children with sickle cell anemia and their healthy siblings.","volume":"97","author":"O Ogunfowora","year":"2005","journal-title":"J. Natl. Med. Assoc."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1531161","DOI":"10.3389\/fpubh.2025.1531161","article-title":"Unveiling the psychosocial and academic implications of living with sickle cell disease among undergraduates in a private university in Nigeria.","volume":"13","author":"O Adeleke","year":"2025 Jan 31","journal-title":"Front. Public Health."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"535-550","DOI":"10.1016\/j.hoc.2018.01.014","article-title":"Key components of pain management for children and adults with sickle cell disease.","volume":"32","author":"A Brandow","year":"2018","journal-title":"Hematol. Oncol. Clin. North Am."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"382-390","DOI":"10.1111\/ejh.14017","article-title":"A multimodal pain protocol for treatment of vaso-occlusive crisis in patients with sickle cell disease: Implementation and evaluation.","volume":"111","author":"M Admiraal","year":"2023 Sep","journal-title":"Eur. J. Haematol."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"3141-3150","DOI":"10.2147\/JPR.S185582","article-title":"Vaso-occlusive crisis in sickle cell disease: Current paradigm on pain management.","volume":"11","author":"S Uwaezuoke","year":"2018","journal-title":"J. Pain Res."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"99-108","DOI":"10.3344\/KJP.2010.23.2.99","article-title":"Pharmacologic management of chronic pain.","volume":"23","author":"C Argoff","year":"2010","journal-title":"Korean J. Pain."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"287-313","DOI":"10.1111\/j.1533-2500.2008.00204.x","article-title":"Opioids and the management of chronic severe pain in the elderly: consensus statement of an International Expert Panel with focus on the six clinically most often used World Health Organization Step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone).","volume":"8","author":"J Pergolizzi","year":"2008 Jul-Aug","journal-title":"Pain Pract."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"562-571","DOI":"10.1001\/jama.2018.22039","article-title":"Effect of Combination of Paracetamol (Acetaminophen) and Ibuprofen vs Either Alone on Patient-Controlled Morphine Consumption in the First 24 Hours After Total Hip Arthroplasty: The PANSAID Randomized Clinical Trial.","volume":"321","author":"K Thybo","year":"2019 Feb 12","journal-title":"JAMA."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"117-133","DOI":"10.1016\/B978-0-12-805455-0.00007-5","article-title":"Pharmacogenomics of abused drugs.","author":"A Dasgupta","year":"January 1, 2017","journal-title":"Alcohol, Drugs, Genes and the Clinical Laboratory."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"e2042-e2052","DOI":"10.1002\/onco.13953","article-title":"Impact of CYP2D6 Pharmacogenomic Status on Pain Control Among Opioid-Treated Oncology Patients.","volume":"26","author":"N Reizine","year":"2021 Nov","journal-title":"Oncologist."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"1801","DOI":"10.3390\/jcm9061801","article-title":"Adverse Drug Reactions in the Emergency Department: Is There a Role for Pharmacogenomic Profiles at Risk?-Results from the ADRED Study.","volume":"9","author":"K Just","year":"2020 Jun 9","journal-title":"J. Clin. Med."},{"key":"ref23","article-title":"Codeine Therapy and CYP2D6 genotype.","author":"L Dean","year":"March 30, 2021","journal-title":"Medical Genetics Summaries."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"269-296","DOI":"10.1146\/annurev. pharmtox.37.1.269","article-title":"Molecular mechanisms of genetic polymorphisms of drug metabolism.","volume":"37","author":"U Meyer","year":"1997","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"1951","DOI":"10.3390\/CANCERS12071951","article-title":"Genetics and opioids: towards more appropriate prescription in cancer pain.","volume":"12","author":"D Bugada","year":"2020","journal-title":"Cancers."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"269-296","DOI":"10.1146\/annurev. pharmtox.37.1.269","article-title":"Molecular mechanisms of genetic polymorphisms of drug metabolism.","volume":"37","author":"U Meyer","year":"1997","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1569-1583","DOI":"10.1517\/17425255.2014.964204","article-title":"Interethnic variability of CYP2D6 alleles and of predicted and measured metabolic phenotypes across world populations.","volume":"10","author":"A Lerena","year":"2014","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"888-896","DOI":"10.1002\/cpt.2149","article-title":"Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid Therapy.","volume":"110","author":"K Crews","year":"2021","journal-title":"Clin. Pharm. Therap."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"295-304","DOI":"10.1016\/j.anclin.2017.01.015","article-title":"Pharmacogenomics in pain management.","volume":"35","author":"R Saba","year":"2017","journal-title":"Anesthesiol. Clin."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"116-124","DOI":"10.1111\/cts.12692","article-title":"Standardizing CYP2D6 genotype to phenotype translation: consensus recommendations from the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group.","volume":"13","author":"K Caudle","year":"2020","journal-title":"Clin. Transl. Sci."},{"key":"ref31","doi-asserted-by":"publisher","DOI":"10.1542\/PEDS.2015-3479","article-title":"Pharmacogenetics for safe codeine use in sickle cell disease.","volume":"138","author":"R Gammal","year":"2016","journal-title":"Pediatrics."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"e0292131","DOI":"10.1371\/journal.pone.0292131","article-title":"Analytical validation of GenoPharm a clinical genotyping open array panel of 46 pharmacogenes inclusive of variants unique to people of African ancestry.","volume":"18","author":"C Kanji","year":"2023","journal-title":"PLoS One."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"8-9","DOI":"10.1182\/blood-2020-140756","article-title":"Prevalence of vaso-occlusive crises in patients with sickle cell disease: A retrospective US claims database analysis.","volume":"136","author":"A Oladapo","year":"2020","journal-title":"Blood."},{"key":"ref34","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-021-02096-6","article-title":"A systematic literature review of frequency of vaso-occlusive crises in sickle cell disease. A systematic literature review of frequency of vaso-occlusive crises in sickle cell disease.","volume":"16","author":"A Zaidi","year":"2021","journal-title":"Orphanet J. Rare Dis."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"93-94","DOI":"10.1089\/bio.2017.0007","article-title":"Genes for life: Biobanking for genetic research in Africa.","volume":"15","author":"E Mayne","year":"2017","journal-title":"Biopreserv. Biobank."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"375-393","DOI":"10.1146\/annurev-genom-083115-022456","article-title":"Broad Consent for genomic research and biobanking: perspectives from low- and middle-income countries.","volume":"17","author":"P Tindana","year":"2016","journal-title":"Annu. Rev. Genom. Hum. Genet."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"9-17","DOI":"10.1111\/dewb.12178","article-title":"\u2018It is an entrustment\u2019: Broad consent for genomic research and biobanks in sub-Saharan Africa.","volume":"19","author":"P Tindana","year":"2019","journal-title":"Dev. World Bioeth."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"1143","DOI":"10.1182\/blood-2023-178129","article-title":"Sickle cell disease management practices across Nigeria: a cross-sectional analysis.","volume":"142","author":"S Ibemere","year":"2023","journal-title":"Blood."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"e21377","DOI":"10.7759\/cureus.21377","article-title":"Health-related quality of life among patients with sickle cell disease in an adult hematology clinic in a tertiary hospital in Lagos, Nigeria.","volume":"14","author":"L Amaeshi","year":"2022","journal-title":"Cureus."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"57-67","DOI":"10.4137\/NMI.S5048","article-title":"The role of nutrition in sickle cell disease.","volume":"3","author":"H Hyacinth","year":"2010","journal-title":"Nutr. Metab. Insights."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1177\/20503121231197866","article-title":"Evidence-based interventions for reducing sickle cell disease-associated morbidity and mortality in sub-Saharan Africa: A scoping review.","volume":"11","author":"E Arji","year":"2023","journal-title":"SAGE Open Med."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"23-24","DOI":"10.1182\/blood-2020-140158","article-title":"The accuracy of physical examination to diagnose anemia among patients 5 years of age or older: A systematic review of the literature.","volume":"136","author":"N Vyas","year":"2020","journal-title":"Blood."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"13","DOI":"10.3389\/fgene.2022.826132","article-title":"Outcome of hydroxyurea use in scd and evaluation of patients\u2019 perception and experience in Nigeria.","volume":"13","author":"R Chianumba","year":"2022","journal-title":"Front. Genet."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"e0276639","DOI":"10.1371\/journal.pone.0276639","article-title":"Determinants of hydroxyurea use among doctors, nurses and sickle cell disease patients in Nigeria.","volume":"17","author":"H Isa","year":"2022","journal-title":"PLoS One."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"765-774","DOI":"10.4314\/ahs.v21i2.36","article-title":"Level of utilization and provider-related barriers to the use of hydroxyurea in the treatment of sickle cell disease patients in Jos, North-Central Nigeria.","volume":"21","author":"A Ofakunrin","year":"2021","journal-title":"Afr. Health Sci."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"12","DOI":"10.3389\/fgene.2021.765958","article-title":"Barriers to therapeutic use of hydroxyurea for sickle cell disease in Nigeria: A cross-sectional survey.","volume":"12","author":"E Okocha","year":"2022","journal-title":"Front. Genet."},{"key":"ref47","article-title":"Clinicians\u2019 Guide to pharmacogenetic testing at clinical labs."},{"key":"ref48","article-title":"Pharmacogenetics panel: Psychotropics."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"798-806","DOI":"10.1111\/cts.12768","article-title":"Primary Care Prescription drug use and related actionable drug-gene interactions in the Danish population.","volume":"13","author":"C Lunenburg","year":"2020","journal-title":"Clin. Transl. Sci."},{"key":"ref50","article-title":"Red cell genotyping - NHS Blood and Transplant."},{"key":"ref51","first-page":"47-54","article-title":"Cytochrome P450 2D6 (CYP2D6) genotype and phenotype determination in the Nigerian populations.","volume":"1","author":"B Ebeshi","year":"2011","journal-title":"Asian J. Pharm. Health Sci."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"1145-1152","DOI":"10.1080\/17512433.2017.1362979","article-title":"Evaluation of CYP2D6 phenotype in the Yoruba Nigerian population.","volume":"10","author":"W Adedeji","year":"2017","journal-title":"Expert Rev. Clin. Pharmacol."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"689-723","DOI":"10.2165\/11318030-000000000-00000","article-title":"Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I.","volume":"48","author":"S Zhou","year":"2009","journal-title":"Clin. Pharmacokinet."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"69-76","DOI":"10.1038\/gim.2016.80","article-title":"Prediction of CYP2D6 phenotype from genotype across world populations.","volume":"19","author":"A Gaedigk","year":"2017","journal-title":"Genet. Med."},{"key":"ref55","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/s40246-022-00378-z","article-title":"Frequencies of CYP2D6 genetic polymorphisms in Arab populations.","volume":"16","author":"M Alali","year":"2022","journal-title":"Hum. Genomics."},{"key":"ref56","doi-asserted-by":"publisher","first-page":"643-659","DOI":"10.1002\/cpt.2749","article-title":"Characterisation of CYP2D6 Pharmacogenetic Variation in Sub-Saharan African Populations.","volume":"113","author":"D Twesigomwe","year":"2023","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref57","doi-asserted-by":"publisher","first-page":"441-446","DOI":"10.1016\/S0022-3565(25)20152-5","article-title":"Frequent distribution of ultrarapid metabolizers of debrisoquine in an Ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles.","volume":"278","author":"E Aklillu","year":"1996","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref58","doi-asserted-by":"publisher","first-page":"484-490","DOI":"10.1038\/s41397-021-00226-8","article-title":"CYP2D6 genotype and reduced codeine analgesic effect in real-world clinical practice.","volume":"21","author":"D Carranza-Leon","year":"2021","journal-title":"Pharmacogenomics J."},{"key":"ref59","doi-asserted-by":"publisher","first-page":"867331","DOI":"10.3389\/fphar.2022.867331","article-title":"The identification of novel CYP2D6 variants in US Hmong: Results from genome sequencing and clinical genotyping.","volume":"13","author":"Y Wen","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref60","doi-asserted-by":"publisher","first-page":"1220-1237","DOI":"10.1002\/cpt.3044","article-title":"PharmVar tutorial on CYP2D6 structural variation testing and recommendations on reporting.","volume":"114","author":"A Turner","year":"2023","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref61","doi-asserted-by":"publisher","first-page":"2025.05.05.25326970","DOI":"10.1101\/2025.05.05.25326970","article-title":"Targeted adaptive sampling enables clinical pharmacogenomics testing and genome-wide genotyping.","author":"P Gan Hui Peng","year":"2025 May 7","journal-title":"medRxiv."},{"key":"ref62","doi-asserted-by":"publisher","first-page":"27-33","DOI":"10.1016\/S0304-3959(98)00021-9","article-title":"Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation.","volume":"76","author":"K Eckhardt","year":"1998","journal-title":"Pain."},{"key":"ref63","doi-asserted-by":"publisher","first-page":"623-626","DOI":"10.1016\/j.jpeds.2007.01.049","article-title":"The effect of CYP2D6 polymorphisms on the response to pain treatment for pediatric sickle cell pain crisis.","volume":"150","author":"D Brousseau","year":"2007","journal-title":"J. Pediatr."},{"key":"ref64","doi-asserted-by":"publisher","first-page":"636-644","DOI":"10.1016\/S0009-9236(96)90211-8","article-title":"The hypoalgesic effect of tramadol in relation to CYP2D6.","volume":"60","author":"L Poulsen","year":"1996","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref65","doi-asserted-by":"publisher","first-page":"257-265","DOI":"10.1038\/sj.tpj.6500406","article-title":"Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication.","volume":"7","author":"J Kirchheiner","year":"2007","journal-title":"Pharmacogenomics J."},{"key":"ref66","doi-asserted-by":"publisher","first-page":"S105-S120","DOI":"10.36076\/ppj.2008\/11\/s105","article-title":"Opioid complications and side effects.","volume":"2s;11","author":"R Benyamin","year":"2008","journal-title":"Pain Physician."},{"key":"ref67","doi-asserted-by":"publisher","first-page":"44-57","DOI":"10.1002\/cpt.2387","article-title":"Pharmacogenomic Clinical Decision Support: A Review, How-to Guide, and Future Vision.","volume":"112","author":"D Wake","year":"2022","journal-title":"Clin. Pharmacol. Ther."}],"container-title":["Gates Open Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/gatesopenresearch.org\/articles\/9-101\/v1\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/gatesopenresearch.org\/articles\/9-101\/v1\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/gatesopenresearch.org\/articles\/9-101\/v1\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T11:45:10Z","timestamp":1762775110000},"score":1,"resource":{"primary":{"URL":"https:\/\/gatesopenresearch.org\/articles\/9-101\/v1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,10]]},"references-count":67,"URL":"https:\/\/doi.org\/10.12688\/gatesopenres.16370.1","relation":{"has-preprint":[{"id-type":"doi","id":"10.12688\/verixiv.1323.2","asserted-by":"subject"},{"id-type":"doi","id":"10.12688\/verixiv.1323.2","asserted-by":"object"}]},"ISSN":["2572-4754"],"issn-type":[{"value":"2572-4754","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,10]]},"assertion":[{"value":"Awaiting Peer Review","URL":"https:\/\/gatesopenresearch.org\/articles\/9-101\/v1#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"Support for this work was provided through grant funding from the Gates Foundation (GF) (Grant Number ID INV-036801). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":0,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}