Pharmacokinetic and neuroimmune pharmacogenetic impacts on slow-release morphine cancer pain control and adverse effects

• Published in: The pharmacogenomics journal Vol. 24; no. 3; p. 18
• Main Authors: Barratt, Daniel T., Klepstad, Pål, Dale, Ola, Kaasa, Stein, Somogyi, Andrew A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2024; Nature Publishing Group
• Subjects: 45/77; 692/1807; 692/308/2056; 692/308/53/2423; 692/499; 692/53/2423; Adult; Aged; Analgesics, Opioid - administration & dosage; Analgesics, Opioid - adverse effects; Analgesics, Opioid - pharmacokinetics; Biomedical and Life Sciences; Biomedicine; Brain-derived neurotrophic factor; Cancer; Cancer Pain - drug therapy; Cancer Pain - genetics; Chi-square test; Collaboration; Constipation; Controlled release; Cytokines; Delayed-Action Preparations - pharmacokinetics; Drug dosages; Female; Gene Expression; Gene polymorphism; Human Genetics; Humans; Interleukin 6 receptors; Male; Metabolites; Middle Aged; Morphine; Morphine - administration & dosage; Morphine - adverse effects; Morphine - pharmacokinetics; Morphine Derivatives - adverse effects; Morphine Derivatives - pharmacokinetics; Narcotics; Nausea; Oncology; Opioids; Pain; Pain management; Pharmacogenetics - methods; Pharmacogenomic Variants; Pharmacokinetics; Pharmacology; Pharmacotherapy; Polymorphism, Single Nucleotide - genetics; Psychopharmacology; Side effects; TLR2 protein; Toll-Like Receptor 2 - genetics; Toll-like receptors
• ISSN: 1470-269X; 1473-1150; 1473-1150
• DOI: 10.1038/s41397-024-00339-w

The aim was to determine if opioid neuroimmunopharmacology pathway gene polymorphisms alter serum morphine, morphine-3-glucuronide and morphine-6-glucuronide concentration-response relationships in 506 cancer patients receiving controlled-release oral morphine. Morphine-3-glucuronide concentrations (standardised to 11 h post-dose) were higher in patients without pain control (median (interquartile range) 1.2 (0.7–2.3) versus 1.0 (0.5–1.9) μM, P  = 0.006), whereas morphine concentrations were higher in patients with cognitive dysfunction (40 (20–81) versus 29 (14–60) nM, P  = 0.02). TLR2 rs3804100 variant carriers had reduced odds (adjusted odds ratio (95% confidence interval) 0.42 (0.22–0.82), P  = 0.01) of opioid adverse events. IL2 rs2069762 G/G (0.20 (0.06-0.52)), BDNF rs6265 A/A (0.15 (0.02–0.63)) and IL6R rs8192284 carrier (0.55 (0.34–0.90)) genotypes had decreased, and IL6 rs10499563 C/C increased (3.3 (1.2–9.3)), odds of sickness response ( P  ≤ 0.02). The study has limitations in heterogeneity in doses, sampling times and diagnoses but still suggests that pharmacokinetics and immune genetics co-contribute to morphine pain control and adverse effects in cancer patients.