Daniela Osteicoechea

Background:  Fentanyl, a potent synthetic opioid used for pain management, has been identified as a contributing factor to the opioid epidemic^1,2. Its pharmacokinetics and pharmacodynamics can vary among individuals, which can lead to unpredictable and potentially harmful effects. Genetic polymorphisms in the enzymes involved in opioid, including fentanyl metabolism have been identified as a factor that may contribute to this variability³.

Research Objectives:  The objective of this paper is to review the current literature on relevant genetic polymorphisms and their role in fentanyl pharmacokinetics and pharmacodynamics.

Methods: A comprehensive literature search was conducted to identify relevant studies published between January 2017 and May 2023, focusing on mechanistic papers.

Results: In terms of opioid pharmacogenomics, it was found that several polymorphic genes, namely an enzyme involved in catecholamine metabolism, COMT, and opioid receptors, OPRM1, and OPRK1, had significant impacts on pain threshold⁴. The COMT haplotypes were found to have a significant influence on the response to morphine for ischemic pain, but the effect of haplotype was opioid-specific and pain modality dependent⁴. The administration of morphine reduced pressure pain threshold in the masseter muscle for the A118G genotype of OPRM1 but not for butorphanol or other pain modalities⁴. In addition, it was found that multiple polymorphisms can affect opioid responses and contribute to inter-person variability.

Regarding fentanyl-specific polymorphisms, patients with polymorphic variants of CYP2D6, i.e., CYP2D6*9 and CYP2D6*29, as well as CYP3A4*1B did not eliminate fentanyl efficiently, leading to higher circulating concentrations ⁷. Individuals carrying the CYP3A4*22 allele had reduced mRNA expression and low CYP3A4 enzyme activity which resulted in higher AUC and lower clearance ⁶. The OPRM1 A118G polymorphism was associated with somnolence, and the COMT G472A polymorphism was also found to increase the risk of somnolence³.Finally, it was found that the COMT high-pain sensitivity haplotype was associated with decreased need for postoperative morphine and that this response is opioid-specific⁶.

Conclusion:  The findings discussed in this abstract highlight the significant impact of genetic polymorphisms in multiple genes on opioid response and adverse drug reactions. The knowledge gained from these studies can aid in the development of personalized opioid therapy that takes into account an individual’s genetic makeup to optimize pain management and minimize adverse effects. Further research in this area is warranted to explore additional genetic variants and their impact on opioid response, as well as to validate the utility of pharmacogenomic-guided opioid therapy in clinical practice.

Works Cited:

1. Lyden J, Binswanger IA. The United States opioid epidemic. Seminars in Perinatology. 2019;43(3):123-131. doi:10.1053/J.SEMPERI.2019.01.001
2. Han Y, Yan W, Zheng Y, Khan MZ, Yuan K, Lu L. The rising crisis of illicit fentanyl use, overdose, and potential therapeutic strategies. Transl Psychiatry 2019 91. 2019;9(1):1-9. doi:10.1038/s41398-019-0625-0
3. Saiz-Rodríguez M, Ochoa D, Herrador C, et al. Polymorphisms associated with fentanyl pharmacokinetics, pharmacodynamics and adverse effects. Basic Clin Pharmacol Toxicol. 2019;124(3):321-329. doi:10.1111/BCPT.13141
4. Ho KWD, Wallace MR, Staud R, Fillingim RB. OPRM1, OPRK1, and COMT genetic polymorphisms associated with opioid effects on experimental pain: a randomized, double-blind, placebo-controlled study. Pharmacogenomics J. 2020;20(3):471-481. doi:10.1038/S41397-019-0131-Z
5. Tang LJ, Han J, Feng YJ, Pu CX, Zhang Y. Comparative study of the efficacy of dexmedetomidine and fentanyl on anxiety and pain of parturients with different COMTva1158met genotypes. BMC Anesthesiol. 2022;22(1):1-7.
6. Matic M, De Hoogd S, De Wildt SN, Tibboel D, Knibbe CAJ, Van Schaik RHN. OPRM1 and COMT polymorphisms: implications on postoperative acute, chronic and experimental pain after cardiac surgery. Pharmacogenomics. 2020;21(3):181-193. doi:10.2217/PGS-2019-0141
7. Grimsrud KN, Ivanova X, Sherwin CM, Palmieri TL, Tran NK. Identification of Cytochrome P450 Polymorphisms in Burn Patients and Impact on Fentanyl Pharmacokinetics: A Pilot Study. J Burn Care Res. 2019;40(1):91. doi:10.1093/JBCR/IRY053