Brazilian Journal of Anesthesiology
https://bjan-sba.org/article/doi/10.1016/j.bjane.2021.09.011
Brazilian Journal of Anesthesiology
Original Investigation

Influence of exogenous opioids on the acute inflammatory response in the perioperative period of oncological surgery: a clinical study

Influência dos opioides exógenos na resposta inflamatória aguda no perioperatório de cirurgia oncológica: estudo clínico

Odirlei João Titon, Joana Perotta Titon, Janaína Carla da Silva, Mariane Okamoto Ferreira, Matheus Ricrado Garbim, Daniel Rech, Janoário Athanazio de Souza, Carolina Panis

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Abstract

Background 
Recently, opioids have been related to trigger changes in cytokine release and tumor angiogenesis processes, influencing tumor growth, metastasis, and recurrence.

Methods
This is a prospective clinical study randomized to test whether if exogenous opioids used in the anesthesia during cancer surgery can affect the systemic inflammatory and immunological patterns. Patients were randomly allocated to the OP (opioid‐inclusive) or OF (opioid-free) anesthesia group. A total of 45 patients were selected, being carriers of prostate, stomach, pancreas, bile ducts, breast, colon, lung, uterus, kidneys, or retroperitoneum tumors. Plasma levels of IL-4, IL-12, IL-17A, and TNF-α, and their oxidative stress profile before and after surgery were evaluated in both groups. In vitro tests were performed by using healthy donor blood incubated with each isolated drug used in patients’ anesthesia for 1 hour, the same cytokines were measured in plasma.

Results
There was a significant reduction in lipid peroxidation in both groups. Patients from OF group had a significant consumption of IL-12 in the perioperative period. The other cytokines evaluated did not vary. It was also observed a significant correlation between IL-12 and TNF-α levels in the OF-post group. Except for atracurium, all tested drugs led to a reduction in IL-12 levels.

Conclusion
This study demonstrated that there is a reduction of IL-12 in the OF-post patients, suggesting acute consumption and that this seems to be a general mechanism of anesthetic drugs, as demonstrated in vitro. Also, these findings bring us to reflect if IL-12 changes may influence the disease progression and recurrence.

Keywords

Opioids;  Cancer;  Cytokines;  Anesthesia

Resumo

Introdução

Recentemente, os opioides têm sido relacionados a desencadear alterações na liberação de citocinas e nos processos de angiogênese tumoral, influenciando o crescimento tumoral, metástase e recorrência.

Métodos

Este é um estudo clínico prospectivo randomizado para testar se os opióides exógenos usados ​​na anestesia durante a cirurgia de câncer podem afetar os padrões inflamatórios e imunológicos sistêmicos. Os pacientes foram alocados aleatoriamente no grupo de anestesia OP (inclusive com opioides) ou OF (sem opioides). Foram selecionados 45 pacientes, portadores de tumores de próstata, estômago, pâncreas, vias biliares, mama, cólon, pulmão, útero, rins ou retroperitônio. Os níveis plasmáticos de IL-4, IL-12, IL-17A e TNF-α e seu perfil de estresse oxidativo antes e após a cirurgia foram avaliados em ambos os grupos. Os testes in vitro foram realizados utilizando sangue de doadores saudáveis incubados com cada medicamento isolado utilizado na anestesia dos pacientes por 1 hora, as mesmas citocinas foram medidas no plasma.

Resultados

Houve redução significativa da peroxidação lipídica em ambos os grupos. Os pacientes do grupo OF tiveram consumo significativo de IL-12 no período perioperatório. As demais citocinas avaliadas não variaram. Também foi observada correlação significativa entre os níveis de IL-12 e TNF-α no grupo OF-pós. Com exceção do atracúrio, todos os medicamentos testados levaram à redução dos níveis de IL-12.

Conclusão

Este estudo demonstrou que há redução de IL-12 nos pacientes pós-FO, sugerindo consumo agudo e que este parece ser um mecanismo geral das drogas anestésicas, conforme demonstrado in vitro. Além disso, esses achados nos levam a refletir se as alterações da IL-12 podem influenciar a progressão e a recorrência da doença.

Palavras-chave

Opioides; Câncer; Citocinas; Anestesia

References

1. Ministério da Saúde (Brasil). Protocolos Clínicos e Diretrizes Terapêuticas em Oncologia. Brasília: Ministério da Saúde; 2014. Available from: http://bvsms.saude.gov. br/bvs/publicacoes/protocolos clinicos diretrizes terapeuticas oncologia.pdf [Accessed February 09, 2019].

2. Bajwa SJ, Anand S, Kaur G. Anesthesia and cancer recurrences: the current knowledge and evidence. J Cancer Res Ther. 2015;11:528–34.

3. Le-Wendling L, Nin O, Capdevila X. Cancer Recurrence and Regional Anesthesia: The Theories, the Data, and the Future in Outcomes. Pain Med. 2016;17:756–75.

4. Tavare AN, Perry NJ, Benzonana LL, et al. Cancer recurrence after surgery: direct and indirect effects of anesthetic agents. Int J Cancer. 2012;130:1237–50.

5. Tedore T. Regional anaesthesia and analgesia: relationship to cancer recurrence and survival. Br J Anaesth. 2015;115:ii34–45.

6. Cakmakkaya OS, Kolodzie K, Apfel CC, et al. Anaesthetic techniques for risk of malignant tumour recurrence. Cochrane Database Syst Rev. 2014:CD008877.

7. Cronin-Fenton DP, Heide-Jørgensen U, Ahern TP, et al. Opioids and breast cancerrecurrence: A Danish population-based cohort study. Cancer. 2015;121:3507–14.

8. Kim R. Effects of surgery and anesthetic choice on immunosuppression and cancer recurrence. J Transl Med. 2018;16:8.

9. Lukoseviciene V, Tikuisis R, Dulskas A, et al. Surgery for triplenegative breast cancer- does the type of anaesthesia have an influence on oxidative stress, inflammation, molecular regulators, and outcomes of disease? J Buon. 2018;23:290–5.

10. Cheng S, Guo M, Liu Z, et al. Morphine promotes the angiogenesis of postoperative recurrent tumors and metastasis of dormant breast cancer cells. Pharmacol. 2019;104:276–86.

11. Nguyen J, Luk K, Vang D, et al. Morphine stimulates cancer progression and mast cell activation and impairs survival in transgenic mice with breast cancer. Br J Anaesth. 2014;113:i4–13.

12. Afsharimani B, Cabot P, Parat MO. Morphine and tumor growth and metastasis. Cancer Metastasis Rev. 2011;30:225–38.

13. Maher DP, Walia D, Heller NM. Suppression of Human Natural Killer Cells by Different Classes of Opioids. Anesth Analg. 2019;128:1013–21.

14. Aich A, Gupta P, Gupta K. Could Perioperative Opioid Use Increase the Risk of Cancer Progression and Metastases? Int Anesthesiol Clin. 2016;54:e1–16.

15. Khabbazi S, Goumon Y, Parat MO. Morphine Modulates Interleukin-4- or Breast Cancer Cell-induced Pro-metastatic Activation of Macrophages. Sci Rep. 2015;5:11389.

16. Sekandarzad MW, van Zundert AAJ, Lirk PB, et al. Perioperative Anesthesia Care and Tumor Progression. Anesth Analg. 2017;124:1697–708.

17. Baumunk D, Strang CM, Kropf S, et al. Impact of thoracic epidural analgesia on blood loss in radical retropubic prostatectomy. Urol Int. 2014;93:193–201.

18. Maher DP, Walia D, Heller NM. Suppression of Human Natural Killer Cells by Different Classes of Opioids. Anesth Analg. 2019;128:1013–21.

19. Moss J, Rosow CE. Development of peripheral opioid antagonists’ new insights into opioid effects. Mayo Clin Proc. 2008;83:1116–30.

20. Singleton PA, Lingen MW, Fekete MJ, et al. Methylnaltrexone inhibits opiate and VEGF-induced angiogenesis: role of receptor transactivation. Microvasc Res. 2006;72:3–11.

21. Lennon FE, Mirzapoiazova T, Mambetsariev B, et al. Overexpression of the -opioid receptor in human non-small cell lung cancer promotes Akt and mTOR activation, tumor growth, and metastasis. Anesthesiology. 2012;116:857–67.

22. Gupta K, Kshirsagar S, Chang L, et al. Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Res. 2002;62:4491–8.

23. Tripolt S, Neubauer HA, Knab VM, et al. Opioids drive breast cancer metastasis through the -opioid receptor and oncogenic STAT3. Neoplasia. 2021;23:270–9.

24. Sen S, Koyyalamudi V, Smith DD, et al. The role of regional anesthesia in the propagation of cancer: A comprehensive review. Best Pract Res Clin Anaesthesiol. 2019;33:507–22.

25. Gach K, Wyrebska ˛ A, Fichna J, et al. The role of morphine in regulation of cancer cell growth. Naunyn Schmiedebergs Arch Pharmacol. 2011;384:221–30.

26. Kwon Y, Hwang SM, Jang JS, et al. Effects of a Preoperative Transdermal Fentanyl Patch on Proinflammatory Cytokine and Pain Levels During the Postoperative Period: A Randomized Controlled Trial. Surg Laparosc Endosc Percutan Tech. 2019;29:339–43.

27. Inada T, Kubo K, Ueshima H, et al. Intravenous anesthetic propofol suppresses prostaglandin E2 production in murine dendritic cells. J Immunotoxicol. 2011;8:359–66.

28. Ko´scielniak-Merak B, Batko I, Kobylarz K, et al. Intravenous, Perioperatively Administered Lidocaine Regulates Serum Pain Modulators’ Concentrations in Children Undergoing Spinal Surgery Pain. Med. 2020;21:1464–73.

29. Zahmatkesh M, Kadkhodaee M, Salarian A, et al. Impact of opioids on oxidative status and related signaling pathways: An integrated view. J Opioid Manag. 2017;13:241–51.

30. Wei J, Luo J, Lv X. How does the anesthetic agent propofol affect tumors? Int J Clin Exp Med. 2017;10:5995–6003.

31. Herrera AC, Victorino VJ, Campos FC, Verenitach BD, Lemos LT, Aranome AM, Oliveira SR, Cecchini AL, Simão AN, Abdelhay E, Panis C, Cecchini R. Impact of tumor removal on the systemic oxidative profile of patients with breast cancer discloses lipid peroxidation at diagnosis as a putative marker of disease recurrence. Clin Breast Cancer. 2014;14(6):451–9, http://dx.doi.org/10.1016/j.clbc.2014.05.002. Epub 2014 Jun 25. PMID: 25077997.


Submitted date:
02/19/2021

Accepted date:
09/05/2021

615eef9fa9539509a8345063 rba Articles
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