The Effect of Polymorphisms in the CYP2D6 and CYP2C9 Genes on the Clinical Efficacy of Tramadol and Ketorolac When Using the Accelerated Recovery Protocol in Patients With Uncomplicated Acute Calculous Cholecystitis Who Underwent Cholecystectomy

Relevance. One of the key components of the accelerated recovery protocols (ARP), in addition to minimizing the surgical approach, is an adequate postoperative analgesia. Despite this, applied postoperative analgesia combinations are not devoid of drawbacks, such as lack of effective postoperative analgesia and the presence of side effect. The use of a pharmacogenetic approach to analgesic therapy for the purpose of its personalization may increase the effectiveness and safety of the use of analgesics. In particular, the presence of an inactive CYP2D6*4 allele , in which the conversion of tramadol to its active metabolite is reduced, contributes to the insufficient efficacy of the drug. As for non-steroidal anti-inflammatory drugs, the presence of CYP2C9*2/*3 polymorphisms leads to a decrease in drug metabolism and a longer half-life, resulting in the increase of the clinical effect and the risk of adverse reactions. Thus, genotyping of patients with the determination of the presence of specific genetic factors can rationalize the postoperative analgesia.

Aim of study. Evaluation of the possible association of polymorphisms of the CYP2D6 and CYP2C9 genes with the clinical efficacy of tramadol and ketorolac in relation to postoperative pain.

Material and methods. This observational clinical study involved 107 patients with uncomplicated acute calculous cholecystitis who underwent videolaparoscopic cholecystectomy and perioperative treatment according to ARP. All patients underwent whole blood sampling followed by real-time polymerase chain reaction genotyping. Analgesic efficacy was assessed using a visual analog scale (VAS) and McGill Pain Questionnaire.

Results. In CYP2D64* carriers pain was higher than that of wild-type carriers, according to VAS and McGill Pain Questionnaire in all investigated periods. In carriers of CYP2C9*2, the pain syndrome was lower than in carriers of the wild type at all intervals studied. In carriers of CYP2C9*3 pain was lower only after 2 and 6 hours, also according to McGill Pain Questionnaire.

Conclusion. 1. The presence of the polymorphic marker CYP2D6*4 may reduce the efficacy of postoperative tramadol analgesia compared with wild type. 2. The presence of the polymorphic marker CYP2C9*2 and CYP2C9*3 may increase the efficacy of ketorolac pain relief compared to wild type.

1. Kehlet H. The stress response to anaesthesia and surgery: release mechanisms and and modifying factors. Clin Anaesthesiol. 1984;2:315–339.

2. Frazee R, Abernathy S, Davis M, Isbell T, Regner J, Smith R. Fast track pathway for perforated appendicitis. Am J Surg. 2017;213(4):739–741. PMID: 27816201 https://doi.org/10.1016/j.amjsurg.2016.08.006

3. Wu C, Raja S. Treatment of acute postoperative pain. Lancet. 2011;377(9784):2215–2225: PMID: 21704871 https://doi.org/10.1016/S0140-6736(11)60245-6

4. Kukes VG, Sychev DA, Ramenskaya GV, Ignat’ev IV. Farmakogenetika sistemy biotransformatsii i transporterov lekarstvennykh sredstv: ot teorii k praktike. Journal Biomed. 2007;(6):29–47. (In Russ.)

5. Evans WE, McLeod HL. Pharmacogenomics — Drug Disposition, Drug Targets, and Side Effects. N Engl J Med. 2003;348(6):538-549: PMID: 12571262 https://doi.org/10.1056/NEJMra020526

6. Crews K, Hicks J, Pui C, Relling MV, Evans WE. Pharmacogenomics and Individualized Medicine: Translating Science Into Practice. Clin Pharmacol Ther. 2012;92(4):467–475: PMID: 22948889 https://doi.org/10.1038/clpt.2012.120

7. Grachev SV, Sychev DA, Ramenskaya GV. Metabolizm lekarstvennykh sredstv. Nauchnye osnovy personalizirovannoy meditsiny. Moscow: GEOTAR-Media Publ.; 2008. (In Russ.)

8. Mercadante S. Opioid metabolism and clinical aspects. Eur J Pharmacol. 2015;769:71–78: PMID: 26522929 https://doi.org/10.1016/j.ejphar.2015.10.049

9. Stamer U, Musshoff F, Kobilay M, Madea B, Hoeft A, Stuber F. Concentrations of tramadol and O-desmethyltramadol enantiomers in different CYP2D6 genotypes. Clin Pharmacol Ther. 2007;82(1):41–47: PMID: 17361124 https://doi.org/10.1038/sj.clpt.6100152

10. Yang Z, Arheart K, Morris R, Morris R, Zhang Y, Rodriguez Y, et al. CYP2D6 poor metabolizer genotype and smoking predict severe postoperative pain in female patients on arrival to the recovery room. Pain Med. 2012;13(4):604–609: PMID: 22497725 https://doi.org/10.1111/j.1526-4637.2012.01296.x

11. Slanar O, Dupal P, Matouskova O, Vondrackova H, Pafko P, Perlik F. Tramadol efficacy in patients with postoperative pain in relation to CYP2D6 and MDR1 polymorphisms. Bratislava Med J. 2012;113(3):152155: PMID: 22428763 https://doi.org/10.4149/bll_2012_036

12. Krasniqi V, Dimovski A, Domjanović I, Bilić I, Božina N. How polymorphisms of the cytochrome P450 genes affect ibuprofen and diclofenac metabolism and toxicity. Arh Hig Rada Toksikol. 2016;67(1):18: PMID: 27092633 https://doi.org/10.1515/aiht-2016-67-2754

13. Llerena A, Alvarez M, Dorado P, González I, Peñas-LLedó E, Pérez B, et al. Interethnic differences in the relevance of CYP2C9 genotype and environmental factors for diclofenac metabolism in Hispanics from Cuba and Spain. Pharmacogenomics J. 2013;14(3):229–234: PMID: 23959274 https://doi.org/10.1038/tpj.2013.28

14. Lee C., Pieper J.A, Frye R, Hinderliter AL, Blaisdell JA, Goldstein JA. Differences in flurbiprofen pharmacokinetics between CYP2C9*1/*1, *1/*2, and *1/*3 genotypes. Eur J Clin Pharmacol Pharmacokinet Dispos. 2003;1(58):791–794: PMID: 12698304 https://doi.org/10.1007/s00228003-0574-6

15. Zhang Y, Zhong D, Si D, Guo Y, Chen X, Zhou H. Lornoxicam pharmacokinetics in relation to cytochrome P450 2C9 genotype. Br J Clin Pharmacol. 2005;59(1):14–17: PMID: 15229460 https://doi.org/10.1016/j.clpt.2004.03.002

16. Vianna-Jorge R, Perini J, Rondinelli E, Suarez-Kurtz G. CYP2C9 genotypes and the pharmacokinetics of tenoxicam in Brazilians*1. Clin Pharmacol Ther. 2004;76(1):18–26: PMID: 15229460 https://doi.org/10.1016/j.clpt.2004.03.002

17. Crews K, Gaedigk A, Dunnenberger H, Leeder JS, Klein TE, Caudle KE, et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for Cytochrome P450 2D6 Genotype and Codeine Therapy: 2014 Update. Clin Pharmacol Ther. 2014;95(4):376–382: PMID: 24458010 https://doi.org/10.1038/clpt.2013.254

18. Balyan R, Mecoli M, Venkatasubramanian R, Chidambaran V, Kamos N, Clay S, et al. CYP2D6 pharmacogenetic and oxycodone pharmacokinetic association study in pediatric surgical patients. Pharmacogenomics. 2017;18(4):337–348: PMID: 28244808 https://doi.org/10.2217/pgs2016-0183

19. Owusu Obeng A, Hamadeh I, Smith M. Review of Opioid Pharmacogenetics and Considerations for Pain Management. Pharmacotherapy. 2017;37(9):1105–1121: PMID: 28699646 https://doi.org/10.1002/phar.1986

20. Orliaguet G, Hamza J, Couloigner V, Denoyelle F, Loriot M-A, Broly F, et al. A Case of Respiratory Depression in a Child With Ultrarapid CYP2D6 Metabolism After Tramadol. Pediatrics. 2015;135(3):753–755: PMID: 25647677 https://doi.org/10.1542/peds.2014-2673

21. Kelly L, Rieder M, van den Anker J, Malkin B, Ross C, Neely MN, et al. More Codeine Fatalities After Tonsillectomy in North American Children. Pediatrics. 2012;129(5):1343–1347: PMID: 22492761 https://doi.org/10.1542/peds.2011-2538

22. Sokolov DA, Lyuboshevskiy PA, Ganert AN. Influence of Cytochrome P-450 Genetic Polymorphisms on the Main and Side Effects of Tramadol in the Postoperative Period. Regional Anesthesia and Acute Pain Management. 2017;11(4):240–246. https://doi.org/10.18821/19936508-2017-11-4-240-246 (In Russ.)

23. Dong H, Lu S, Zhang R, Liu D-D, Zhang Y-Z, Song C-Y. Effect of the CYP2D6 gene polymorphism on postoperative analgesia of tramadol in Han nationality nephrectomy patients. Eur J Clin Pharmacol. 2015;(246):681–686: PMID: 25948472 https://doi.org/10.1007/s00228015-1857-4

24. Wang G, Zhang H, He F, Fang XM. Effect of the CYP2D6*10 C188T polymorphism on postoperative tramadol analgesia in a Chinese population. Eur J Clin Pharmacol. 2006;62(11):927–931: PMID: 16960721 https://doi.org/10.1007/s00228-006-0191-2

25. Martínez C, Blanco G, Ladero J, García-Martín E, Taxonera C, Gamito FG, et al. Genetic predisposition to acute gastrointestinal bleeding after NSAIDs use. Br J Pharmacol. 2004;141(2):205–208: PMID: 14707031 https://doi.org/10.1038/sj.bjp.0705623

26. Agúndez J, García-Martín E, Martínez C. Genetically based impairment in CYP2C8- and CYP2C9-dependent NSAID metabolism as a risk factor for gastrointestinal bleeding: Is a combination of pharmacogenomics and metabolomics required to improve personalized medicine? Expert Opin Drug Metab Toxicol. 2009;5(6):607–620: PMID: 19422321 https://doi.org/10.1517/17425250902970998

27. Murto K, Lamontagne C, McFaul C, MacCormick J, Ramakko K-A, Aglipay M, et al. Celecoxib pharmacogenetics and pediatric adenotonsillectomy: a double-blinded randomized controlled study. Can J Anaesth. 2015;62(7):785–797: PMID: 25846344 https://doi.org/10.1007/s12630015-0376-1

28. Calvo A, Zupelari-Gonçalves P, Dionísio T, Brozoski DT, Faria FA, Santos CF. Efficacy of piroxicam for postoperative pain after lower third molar surgery associated with CYP2C8*3 and CYP2C9. J Pain Res. 2017;10:1581–1589: PMID: 28740425 https://doi.org/10.2147/JPR.S138147

29. Rollason V, Samer CF, Daali Y, Desmeules JA. Prediction by Pharmacogenetics of Safety and Efficacy of Non-Steroidal AntiInflammatory Drugs: A Review. Curr Drug Metab. 2014;15(3):326–343: PMID: 24524667 https://doi.org/10.2174/138920021566614020221445