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CYP450 polymorphisms and clinical pharmacogenetics of ibuprofen after lower third molar extraction

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

This study hypothesized that drugs accumulate in the bloodstream of poor-metabolizing patients and may have more adverse effects and different pain perceptions and aimed to investigate the influence of CYP450 polymorphisms on acute postoperative pain, swelling, and trismus controlled by ibuprofen (600 mg) in 200 volunteers after dental extraction. In addition, surgical outcomes can determine pain, edema, and trismus and indicate inflammatory reactions after oral surgeries.

Methods

Genetic sequencing was performed to identify CYP450 polymorphisms and the surgical parameters evaluated: pre and postoperative swelling, trismus, and temperature; self-reported postoperative pain with visual analog scale (VAS); rescue medication consumed; and severity of adverse reactions.

Results

A multiple linear regression model with independent variables [single nucleotide polymorphisms (SNPs), BMI (body mass index), duration, and difficulty of surgery] and dependent variables [postoperative pain by sum of pain intensity difference (SPID), trismus, and swelling] was used for analysis. The duration of surgery was a predictor for pain at 8 h and 96 h after surgery, and BMI was a predictor for both swelling and trismus on the 2nd postoperative day. When evaluating CYP2C8 and C9 genotyped SNPs, it was observed that normal metabolizers showed higher pain levels than the intermediate/poor metabolizers on the postoperative periods as compared with time 0 h. In another analysis, the poor metabolizers for CYP2C8 and C9 presented lower levels of postoperative pain after 8 h and used rescue medication earlier than normal metabolizers.

Conclusion

Ibuprofen 600 mg was very effective in controlling inflammatory pain after lower third molar surgeries, without relevant adverse reactions; although in a very subtle way, patients with poor metabolism had higher levels of pain in the first hours, and no longer after 8 h, and used pain relief medication earlier.

Trial registration

The study was registered with ClinicalTrials.gov ID (NCT03169127), on March 16th, 2017.

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Data availability

Data supporting the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

References

  1. Meyer UA (2004) Pharmacogenetics - five decades of therapeutic lessons from genetic diversity. Nat Rev Genet 5:669–676

    Article  CAS  Google Scholar 

  2. Martínez C, García-Martín E, Blanco G et al (2005) The effect of the cytochrome P450 CYP2C8 polymorphism on the disposition of (R)-ibuprofen enantiomer in healthy subjects. Br J Clin Pharmacol 59:62–68. https://doi.org/10.1111/j.1365-2125.2004.02183.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. García-Martín E, Martínez C, Tabarés B et al (2004) Interindividual variability in ibuprofen pharmacokinetics is related to interaction of cytochrome P450 2C8 and 2C9 amino acid polymorphisms. Clin Pharmacol Ther 76:119–127. https://doi.org/10.1016/j.clpt.2004.04.006

    Article  CAS  PubMed  Google Scholar 

  4. Martínez C, Blanco G, Ladero JM, García-Martín E, Taxonera C, Gamito FG, Diaz-Rubio M, Agúndez JAG (2004) Genetic predisposition to acute gastrointestinal bleeding after NSAIDs use. Br J Pharmacol 141:205–208. https://doi.org/10.1038/sj.bjp.0705623

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sanderson S, Emery J, Higgins J (2005) CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet™ systematic review and meta-analysis. Genet Med 7:97–104

    Article  CAS  Google Scholar 

  6. Agúndez JAG, García-Martín E, Martínez C (2009) 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 5:607–620. https://doi.org/10.1517/17425250902970998

    Article  PubMed  Google Scholar 

  7. Senagore AJ, Champagne BJ, Dosokey E, Brady J, Steele SR, Reynolds HL, Stein SL, Delaney CP (2017) Pharmacogenetics-guided analgesics in major abdominal surgery: further benefits within an enhanced recovery protocol. Am J Surg 213:467–472. https://doi.org/10.1016/j.amjsurg.2016.11.008

    Article  PubMed  Google Scholar 

  8. Calvo AM, Zupelari-Gonçalves P, Dionísio TJ, Brozoski D, Faria FA, Santos C (2017) Efficacy of piroxicam for postoperative pain after lower third molar surgery associated with CYP2C8*3 and CYP2C9. J Pain Res Volume 10:1581–1589. https://doi.org/10.2147/JPR.S138147

    Article  Google Scholar 

  9. Matsunaga M, Isowa T, Murakami H, Kasugai K, Yoneda M, Kaneko H, Ohira H (2009) Association of polymorphism in the human μ-opioid receptor OPRM1 gene with proinflammatory cytokine levels and health perception. Brain Behav Immun 23:931–935. https://doi.org/10.1016/j.bbi.2009.03.007

  10. Gregorio LVL, Giglio FPM, Sakai VT, Modena KCS, Colombini BL, Calvo AM, Sipert CR, Dionísio TJ, Lauris JRP, Faria FAC, Trindade AS Junior, Santos CF (2008) A comparison of the clinical anesthetic efficacy of 4% articaine and 0.5% bupivacaine (both with 1:200,000 epinephrine) for lower third molar removal. Oral surgery. Oral Med Oral Pathol Oral Radiol Endodontology 106:19–28. https://doi.org/10.1016/j.tripleo.2007.11.024

  11. Weckwerth G, Simoneti L, Zupelari-Goncalves P, Calvo A.M., Brozoski D.T., Dionisio T.J., Torres E.A., Lauris J.R.P., Faria F.A.C., Santos C.F. (2016) Efficacy of naproxen with or without esomeprazole for pain and inflammation in patients after bilateral third molar extractions: a double blinded crossover study. Med Oral Patol Oral Cir Bucal 22:0–0. https://doi.org/10.4317/medoral.21514

  12. Zupelari-Goncalves P, Weckwerth GMM, Calvo AMM et al (2017) Efficacy of oral diclofenac with or without codeine for pain control after invasive bilateral third molar extractions. Int J Oral Maxillofac Surg 46:621–627. https://doi.org/10.1016/j.ijom.2017.01.008

    Article  CAS  PubMed  Google Scholar 

  13. Trindade PAK, Giglio FPM, Colombini-Ishikiriama BL, Calvo AM, Modena KCS, Ribeiro DA, Dionísio TJ, Brozoski DT, Lauris JRP, Faria FAC, Santos CF (2012) Sublingual ketorolac and sublingual piroxicam are equally effective for postoperative pain, trismus, and swelling management in lower third molar removal. Oral Surg Oral Med Oral Pathol Oral Radiol 114:27–34. https://doi.org/10.1016/j.tripleo.2011.05.027

    Article  PubMed  Google Scholar 

  14. Senes AM, Calvo AM, Colombini-Ishikiriama BL, Gonçalves PZ, Dionísio TJ, Sant’ana E, Brozoski DT, Lauris JRP, Faria FAC, Santos CF (2015) Efficacy and safety of 2% and 4% Articaine for lower third molar surgery. J Dent Res 94:166S–173S. https://doi.org/10.1177/0022034515596313

    Article  CAS  PubMed  Google Scholar 

  15. Trindade PAK, Giglio FPM, Colombini-Ishikiriama BL, Calvo AM, Modena KCS, Ribeiro DA, Dionísio TJ, Brozoski DT, Lauris JRP, Faria FAC, Santos CF (2011) Comparison of oral versus sublingual piroxicam during postoperative pain management after lower third molar extraction. Int J Oral Maxillofac Surg 40:292–297. https://doi.org/10.1016/j.ijom.2010.10.026

    Article  CAS  PubMed  Google Scholar 

  16. Calvo AM, Brozoski DT, Giglio FPM, Gonçalves PZ, Sant'ana E, Dionísio TJ, Lauris JRP, Santos CF (2012) Are antibiotics necessary after lower third molar removal? Oral Surg Oral Med Oral Pathol Oral Radiol 114:S199–S208. https://doi.org/10.1016/j.oooo.2011.10.022

    Article  PubMed  Google Scholar 

  17. Simoneti LF, Weckwerth GM, Dionísio TJ, Torres EA, Zupelari-Gonçalves P, Calvo AM, Lauris JR, Faria FC, Santos CF (2018) Efficacy of ketoprofen with or without omeprazole for pain and inflammation control after third molar removal. Braz Dent J 29:140–149. https://doi.org/10.1590/0103-6440201802254

    Article  PubMed  Google Scholar 

  18. Martire LM, Wilson SJ, Small BJ, Conley YP, Janicki PK, Sliwinski MJ (2016) COMT and OPRM1 genotype associations with daily knee pain variability and activity induced pain. Scand J Pain 10:6–12. https://doi.org/10.1016/j.sjpain.2015.07.004

    Article  PubMed  PubMed Central  Google Scholar 

  19. Jensen MP, Martin SA, Cheung R (2005) The meaning of pain relief in a clinical trial. J Pain 6:400–406. https://doi.org/10.1016/j.jpain.2005.01.360

    Article  PubMed  Google Scholar 

  20. Chou WY, Yang LC, Lu HF, Ko JY, Wang CH, Lin SH, Lee TH, Concejero A, Hsu CJ (2006) Association of μ-opioid receptor gene polymorphism (A118G) with variations in morphine consumption for analgesia after total knee arthroplasty. Acta Anaesthesiol Scand 50:787–792. https://doi.org/10.1111/j.1399-6576.2006.01058.x

    Article  CAS  PubMed  Google Scholar 

  21. Zhang Y, Wang D, Johnson AD, Papp AC, Sadée W (2005) Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G. J Biol Chem 280:32618–32624. https://doi.org/10.1074/jbc.M504942200

    Article  CAS  PubMed  Google Scholar 

  22. Bartošová O, Polaneckỳ O, Perlík F et al (2015) OPRM1 and ABCB1 polymorphisms and their effect on postoperative pain relief with piritramide. Physiol Res 64:S521–S527

    Article  Google Scholar 

  23. Cooper SA, Desjardins PJ, Turk DC, Dworkin RH, Katz NP, Kehlet H, Ballantyne JC, Burke LB, Carragee E, Cowan P, Croll S, Dionne RA, Farrar JT, Gilron I, Gordon DB, Iyengar S, Jay GW, Kalso EA, Kerns RD, McDermott MP, Raja SN, Rappaport BA, Rauschkolb C, Royal MA, Segerdahl M, Stauffer JW, Todd KH, Vanhove GF, Wallace MS, West C, White RE, Wu C (2016) Research design considerations for single-dose analgesic clinical trials in acute pain: IMMPACT recommendations. Pain 157:288–301

    Article  Google Scholar 

  24. Troullos ES, Hargreaves KM, Butler DP, Dionne RA (1990) Comparison of nonsteroidal anti-inflammatory drugs, ibuprofen and flurbiprofen, with methylprednisolone and placebo for acute pain, swelling, and trismus. J Oral Maxillofac Surg 48:945–952. https://doi.org/10.1016/0278-2391(90)90007-O

    Article  CAS  PubMed  Google Scholar 

  25. Graziani F, D’Aiuto F, Arduino PG, Tonelli M, Gabriele M (2006) Perioperative dexamethasone reduces post-surgical sequelae of wisdom tooth removal. A split-mouth randomized double-masked clinical trial. Int J Oral Maxillofac Surg 35:241–246. https://doi.org/10.1016/j.ijom.2005.07.010

    Article  CAS  PubMed  Google Scholar 

  26. Antunes AA, Avelar RL, Neto ECM et al (2011) Effect of two routes of administration of dexamethasone on pain, edema, and trismus in impacted lower third molar surgery. Oral Maxillofac Surg 15:217–223. https://doi.org/10.1007/s10006-011-0290-9

    Article  PubMed  Google Scholar 

  27. Pérez-González JM, Esparza-Villalpando V, Martínez-Rider R, Noyola-Frías MÁ, Pozos-Guillén A (2018) Clinical and radiographic characteristics as predictive factors of swelling and trismus after mandibular third molar surgery: a longitudinal approach. Pain Res Manag 2018:1–6. https://doi.org/10.1155/2018/7938492

    Article  Google Scholar 

  28. de Santana-Santos T, de Souza-Santos J, Martins-Filho P, da Silva LCF, de Oliveira e Silva ED, Gomes ACA (2013) Prediction of postoperative facial swelling, pain and trismus following third molar surgery based on preoperative variables. Med Oral Patol Oral Cir Bucal 18:e65–e70. https://doi.org/10.4317/medoral.18039

    Article  PubMed  Google Scholar 

  29. Preissner SC, Hoffmann MF, Preissner R, Dunkel M, Gewiess A, Preissner S (2013) Polymorphic cytochrome P450 enzymes (CYPs) and their role in personalized therapy. PLoS One 8:1–12. https://doi.org/10.1371/journal.pone.0082562

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  31. Wu X, Zuo J, Guo T, Yuan L (2013) CYP2C8 polymorphism frequencies among Han, Uighur, Hui, and Mongolian Chinese populations. Genet Test Mol Biomarkers 17:104–108. https://doi.org/10.1089/gtmb.2012.0256

    Article  CAS  PubMed  Google Scholar 

  32. López-Rodríguez R, Novalbos J, Gallego-Sandín S et al (2008) Influence of CYP2C8 and CYP2C9 polymorphisms on pharmacokinetic and pharmacodynamic parameters of racemic and enantiomeric forms of ibuprofen in healthy volunteers. Pharmacol Res 58:77–84. https://doi.org/10.1016/j.phrs.2008.07.004

    Article  CAS  PubMed  Google Scholar 

  33. Krasniqi V, Dimovski A, Domjanovic IK et al (2016) How polymorphisms of the cytochrome P450 genes affect ibuprofen and diclofenac metabolism and toxicity. Arh Hig Rada Toksikol 67:1–8. https://doi.org/10.1515/aiht-2016-67-2754

    Article  CAS  PubMed  Google Scholar 

  34. Lustenberger FD, Grätz KW, Mutzbauer TS (2011) Efficacy of ibuprofen versus lornoxicam after third molar surgery: a randomized, double-blind, crossover pilot study. Oral Maxillofac Surg 15:57–62. https://doi.org/10.1007/s10006-010-0255-4

    Article  PubMed  Google Scholar 

  35. Albuquerque AFM, Fonteles CSR, do Val DR et al (2017) Effect of pre-emptive analgesia on clinical parameters and tissue levels of TNF-α and IL-1β in third molar surgery: a triple-blind, randomized, placebo-controlled study. Int J Oral Maxillofac Surg 46:1615–1625. https://doi.org/10.1016/j.ijom.2017.05.007

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank the São Paulo Research Foundation (FAPESP), process number 2016/12671-5 and 2018/04157-5, and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brazil (CAPES)—Finance Code 001. The authors would like to thank Viviane Aparecida Parisi Santos, Thais Francini Garbieri, Bruno Freitas Trevizo, and Marina Morettin Zupelari for their help with the data collection. The authors would also like to thank Kailos Genetics Inc. and HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA, for their contribution to this study.

Funding

This research received financial support from the São Paulo Research Foundation (FAPESP), process number 2016/12671–5 and 2018/04157–5. This study was also financed partly by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brazil (CAPES)—Finance Code 001.

Author information

Authors and Affiliations

  1. Discipline of Pharmacology, Bauru School of Dentistry, Department of Biological Sciences, University of São Paulo, Alameda Dr. Octávio Pinheiro Brisolla, 9-75, Bauru, SP, 17012-901, Brazil

    Giovana M. Weckwerth, Thiago J. Dionísio, Gabriela M. Oliveira, Elza A. Torres, Leonardo R. Bonjardim, Adriana M. Calvo & Carlos F. Santos

  2. Piracicaba Dental School, Department of Physiological Sciences, University of Campinas, Piracicaba, SP, Brazil

    Yuri M. Costa

  3. Bauru School of Dentistry, Department of Pediatric Dentistry, Orthodontics and Community Health, University of São Paulo, Bauru, SP, Brazil

    Bella L. Colombini-Ishiquiriama

  4. Kailos Genetics Inc., Huntsville, AL, USA

    Troy Moore

  5. HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA

    Devin M. Absher

Authors
  1. Giovana M. Weckwerth
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  2. Thiago J. Dionísio
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  3. Yuri M. Costa
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  4. Bella L. Colombini-Ishiquiriama
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  5. Gabriela M. Oliveira
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  6. Elza A. Torres
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  7. Leonardo R. Bonjardim
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  8. Adriana M. Calvo
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  9. Troy Moore
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  11. Carlos F. Santos
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Contributions

G. M. Weckwerth performed all surgeries, all laboratory experiments, genetic sequencing, and analyzed the data. T. J. Dionísio and Y. M. Costa provided and analyzed the primary data. B. L. Colombini-Ishiquiriama, G. M. Oliveira, and E. A. Torres were essential in the execution of all surgeries and data collections during the patient’s treatment and provided primary data. T. Moore and D. M. Absher developed and supervised all genetic sequencing performed at Kailos Genetics Inc. in association with HudsonAlpha Institute for Biotechnology. A.M. Calvo, L. R. Bonjardim, and C. F. Santos contributed to the study design, supervised the experiments, reviewed, and edited the manuscript. All authors approved the final version of the article, including the authorship list.

Corresponding author

Correspondence to Carlos F. Santos.

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Conflict of interest

The authors declare that there are no conflicts of interest regarding the publication of this paper.

Ethical approval

This research was approved by the Institutional Ethics Committees of the Bauru School of Dentistry (FOB), University of São Paulo (USP) Bauru, SP, Brazil, and by the National Commission of Ethics Research (CONEP), Brazil National Research Ethics System (CAAE number: 59807716.9.0000.5417).

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Weckwerth, G.M., Dionísio, T.J., Costa, Y.M. et al. CYP450 polymorphisms and clinical pharmacogenetics of ibuprofen after lower third molar extraction. Eur J Clin Pharmacol 77, 697–707 (2021). https://doi.org/10.1007/s00228-020-03046-0

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  • DOI: https://doi.org/10.1007/s00228-020-03046-0

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