Risk stratification for opioid analgesia failure in cancer patients using pharmacogenetic markers

Khaytovich E.D., Shikh E.V., Kazakov R.E.

1) I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia; 2) Scientific Center for Expertise of Medical Products, Ministry of Health of the Russian Federation, Moscow, Russia

Background: Morphine is the drug of choice for pain relief in cancer patients; however, interindividual variability in drug response limits the effectiveness of standard doses. The introduction of pharmacogenetic approaches allows for personalized selection of opioid therapy, improving its safety and efficacy.
Objective: Evaluation of the association between OPRM1 (rs1799971), COMT (rs4680), CYP2D6 (*4, *10), and ABCB1 (rs1045642) gene polymorphisms and the need for morphine dose titration in palliative cancer patients, taking into account pharmacokinetic and clinical parameters.
Materials and methods: The study included 86 palliative care cancer patients receiving morphine as their primary analgesic. All participants underwent genotyping for the aforementioned polymorphisms. Plasma morphine concentrations were determined using HPLC-MS/MS. Pain was assessed using a visual analog scale (VAS) at three time points. Based on a combination of genetic factors, an integrated genetic risk scale (0–7 points) was developed, reflecting the likelihood of standard dose ineffectiveness. 
Results: The analysis showed that in patients with a high score (5-7 points), dose titration was required in 81% of cases, compared to only 5% of those with a low score (0-1 point). A weak relationship between pain severity and steady-state morphine concentration was found, indicating genetically determined resistance. Personalized dosage selection based on the pharmacogenetic profile enabled therapeutic concentrations and clinically significant pain reduction (VAS ≤ 3) to be achieved without excessive drug exposure.
Conclusion: Pharmacogenetic profiling based on OPRM1, COMT, CYP2D6, and ABCB1 analysis predicts the risk of insufficient analgesia with a standard dose of morphine in cancer patients. The developed integrated scale can be used to stratify patients and select the starting dose of opioid therapy, thereby increasing its efficacy and safety. 

For citations: Khaytovich E.D., Shikh E.V., Kazakov R.E. Risk stratification for opioid analgesia failure in cancer patients using pharmacogenetic markers. Pharmateca. 2025;32(9):126-137. (In Russ.). DOI: https://dx.doi.org/10.18565/pharmateca.2025.9.126-137

Authors’ contribution: E.D. Khaytovich developed the study concept and design, formed patient groups, collected clinical material, analyzed and interpreted the data, and prepared the initial version of the manuscript. E.V. Shikh provided scientific supervision at all stages of the study, developed the research hypothesis, revised the study design, and critically revised the manuscript. R.E. Kazakov performed pharmacogenetic testing and processed and verified laboratory data.
Conflicts of interest: The authors confirm that they have no conflicts of interest to declare.
Funding: The study was conducted without any sponsorship.
Ethical Approval: The study was approved by the local ethics committee of the I.M. Sechenov First Moscow State Medical University (protocol No. 01-21 dated January 22, 2021).
Patient Consent for Publication: All patients provided informed consent for the publication of their data.
Authors’ Data Sharing Statement: The data supporting the findings of this study are available upon request from the corresponding author after approval from the principal investigator.

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About the Authors

Evgeny D. Khaytovich, Postgraduate Student, Department of Clinical Pharmacology and Propaedeutics of Internal Medicine, Clinical Pharmacologist, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia; eukhad@gmail.com, ORCID: https://orcid.org/0000-0003-2629-9250 (corresponding author)
Evgenia V. Shikh, Dr. Sci. (Med.), Professor, Corresponding Member of the Russian Academy of Sciences, Head of the Department of Clinical Pharmacology and Propaedeutics of Internal Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia; chih@mail.ru, ORCID: https://orcid.org/0000-0001-6589-7654
Ruslan E. Kazakov, Cand. Sci. (Biol.), Leading Researcher, Scientific Center for Expertise of Medical Products, Ministry of Health of the Russian Federation, Moscow, Russia; rustic100@rambler.ru, ORCID: https://orcid.org/0000-0003-0802-4229

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