Effect of genetic polymorphisms and haplotypes on the efficacy and safety of postoperative analgesia with ketoprofen in patients with coronary artery disease after cardiac surgery
Authors: Shatskiy D A , Morozova T E , Shikh N V , Shikh E V , Andrushchyshina T B , Lukina M V , Kachanova A A , Sozaeva Z A , Abdullaev S P , Denisenko N P , Akmalova K A , Sychev D A 
Published: October 2021

Abstract

Background
Most cardiac surgeries are associated with post-sternotomy pain syndrome. Pain causes elevation of blood pressure, heart rate and may be associated with hemodynamic instability, respiratory infections, and other postoperative complications. Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used analgesics in cardiac surgery. The majority of NSAIDs are metabolized by cytochrome P-450. The mechanism of action of NSAIDs is associated with blocking of prostaglandin-endoperoxide synthase (PTGS). Individual variabilities and gene polymorphisms may affect ketoprofen exposure, efficacy and safety.

Purpose
Evaluation of the influence of CYP2C9 - CYP2D6 and PTGS-2 rs20417 – PTGS-1 rs12353214 haplotypes on the efficacy and safety of postoperative analgesia with ketoprofen in patients with coronary artery disease after cardiac surgery.

Methods
The study included 90 patients. Pain intensity assessment was measured by the Numeric Rating Scale (NRS). Dyspeptic symptoms were evaluated using the Gastrointestinal Symptom Rating Scale (GSRS). Acute kidney injury was determined by Kidney Disease Improving Global Outcomes criteria. Genotyping of polymorphisms CYP2C9*3 (1075A&gt;C) rs1057910, CYP2D6*4 (1846G&gt;A) rs3892097, PTGS-2 (G&gt;C) rs20417, PTGS-1 (C&gt;T) rs12353214 was performed.

Results
The study revealed the following haplotypes: (1) CYP2C9*3 rs1057910 (AA) – CYP2D6*4 rs3892097 (GG), (2) CYP2C9*3 rs1057910 (AC) – CYP2D6*4 rs3892097 (GA), (3) PTGS-2 rs20417 (GG) – PTGS-1 rs12353214 (CT), (4) PTGS-2 rs20417 (CC) – PTGS-1 rs12353214 (CC). Pain intensity by the NRS score was significantly higher in patients with AA-GG haplotype compared to AC-GA haplotype for CYP2C9*3 - CYP2D6*4: 7,13±2,14 and 5±1,52 (p=0,009); 7,06±1,99 and 4,86±1,57 (p=0,007); 4,96±1,83 and 3,29±1,79 (p=0,04); 4,57±1,66 and 2,86±1,57 (p=0,02), on days 1, 2, 3 and 5 in the postoperative period, respectively. There were no significant differences in pain intensity by the NRS in patients with PTGS-2 rs20417 – PTGS-1 rs12353214 haplotypes. Also there were no significant differences in GSRS score and acute kidney injury frequency in patients with AA-GG and AC-GA haplotypes for CYP2C9*3 – CYP2D6*4 and GG-CT and CC-CC haplotypes for PTGS-2 rs20417 – PTGS-1 rs12353214.

Conclusion
CYP2C9*3 - CYP2D6*4 haplotypes affect efficacy of postoperative analgesia with ketoprofen in patients with coronary artery disease after cardiac surgery. Further studies are needed to develop genotype-guided postoperative pain management.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This study was financially supported by RF President's grant for scientific schools, project No. NSh 2698.2020.7 Pain intensity by NRSDyspepsia symptoms by GSRS