Impact of Genetic Variants on Postoperative Pain and Fentanyl Dose Requirement in Patients Undergoing Major Breast Surgery: A Candidate Gene Association Study
Authors: Kumar Shathish , Kesavan Ramasamy , Sistla Sarath Chandra , Penumadu Prasanth , Natarajan Harivenkatesh , Nair Sreekumaran , Chakradhara Rao Uppugunduri S. , Venkatesan Vasuki , Kundra Pankaj 
Published: December 2022

BACKGROUND:
Postoperative analgesia is crucial for the early and effective recovery of patients undergoing surgery. Although postoperative multimodal analgesia is widely practiced, opioids such as fentanyl are still one of the best analgesics. The analgesic response of fentanyl varies widely among individuals, probably due to genetic and nongenetic factors. Among genetic factors, single nucleotide polymorphisms (SNPs) may influence its analgesic response by altering the structure or function of genes involved in nociceptive, fentanyl pharmacodynamic, and pharmacokinetic pathways. Thus, it is necessary to comprehensively ascertain if the SNPs present in the aforementioned pathways are associated with interindividual differences in fentanyl requirement. In this study, we evaluated the association between 10 candidate SNPs in 9 genes and 24-hour postoperative fentanyl dose (primary outcome) and also with postoperative pain scores and time for first analgesia (secondary outcomes).

METHODS:
A total of 257 South Indian women, aged 18–70 years, with American Society of Anesthesiologists (ASA) physical status I–III, undergoing major breast surgery under general anesthesia, were included in the study. Patients were genotyped for candidate SNPs using real-time polymerase chain reaction. All patients received a standardized intravenous fentanyl infusion through a patient-controlled analgesic (PCA) pump, and the 24-hour postoperative fentanyl dose requirement was measured using PCA.

RESULTS:
The median 24-hour postoperative fentanyl requirement was higher in rs1799971 carriers (G/G versus A/A + A/G—620 μg [500–700] vs 460 μg [400–580]) with a geometric mean (GM) ratio of 1.91 (95% confidence interval [CI], 1.071–1.327). The median 24-hour pain scores were higher in rs4680 carriers (A/G + A/A versus G/G—34 [30–38] vs 31 [30–38]) with a GM ratio of 1.059 (95% CI, 1.018–1.101) and were lower in rs1045642 carriers (A/A + A/G versus G/G—34 [30–38] vs 30 [30–34]) with a GM ratio of 0.936 (95% CI, 0.889–0.987). The median time for first analgesic was lower in rs734784 carriers [C/C versus T/T + C/T—240 minutes (180–270) vs 240 minutes (210–270)] with a GM ratio of 0.902 (95% CI, 0.837–0.972). Five of 9 clinical factors, namely, history of diabetes, hypertension, hypothyroidism, anesthesia duration, and intraoperative fentanyl requirement were associated with different outcomes individually (P < .05) and were used to adjust the respective associations.

CONCLUSIONS:
The SNP opioid receptor mu-1 (OPRM1) (rs1799971) was associated with higher postoperative fentanyl requirement in South Indian patients undergoing major breast surgery. Twenty-four hour postoperative pain scores were higher in catechol-O-methyl transferase (COMT) (rs4680) carriers and lower in ATP binding cassette subfamily B member 1 (ABCB1) (rs1045642) carriers, whereas time for first analgesic was lower in potassium channel subunit 1 (KCNS1) (rs734784) carriers. However, these exploratory findings must be confirmed in a larger study.